Adamantyl diamide derivatives and uses of same

ABSTRACT

The present invention provides adamantyl-diamide derivatives of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 2  are as defined herein, or a pharmaceutically acceptable salt thereof; and pharmaceutical compositions and methods using the same.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. Divisional patent application claimingthe benefit of U.S. Nonprovisional patent application Ser. No.12/075,212 filed on Mar. 30, 2011, which claims benefit toNonprovisional patent application Ser. No. 12/504,711 filed Jul. 17,2009, which claims benefit to Provisional Applications Nos. 61/083,563and 61/160,804 filed Jul. 25, 2008 and Mar. 17, 2009, respectively, eachof which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention provides adamantyl diamide derivatives, as well aspharmaceutical compositions and methods of treatment using same.

BACKGROUND OF THE INVENTION

This invention concerns adamantyl diamide derivatives, which act asallosteric modulators of the metabotropic glutamate receptor 5 (mGlu5receptors or mGluR5), as well as pharmaceutical compositions and methodsof treatment utilizing these compounds.

Glutamate is the major excitatory neurotransmitter in the mammaliancentral nervous system. One means of modulating glutamateneurotransmission is through metabotropic glutamate receptors (mGluRs);another means being ionotropic receptors. Presently, eight mGluRs havebeen cloned and classified into three groups based on sequence homology,preferred signal transduction pathway and pharmacology. Group I ofmGluRs includes mGluR1 and mGluR5, while Group II comprises mGluR2 andmGluR3 and Group 111 comprises mGlu4, 6, 7 and 8 receptors.

mGlu receptors have an essential role in normal brain functions, as wellas in neurological, psychiatric, and neuromuscular disorders. mGlu5receptors are located primarily postsynaptically and highly expressed inthe limbic brain regions. mGlu5 receptors also are expressed in thethalamus, spinal cord, and vagal nerve systems, as well as peripherallyin the skin on nerve endings and C fibers.

Ligands to the mGlu5 receptors have been shown to have promise forperipheral and central nervous system disorders. See e.g., G. Jaeschkeet al., “mGlu5 receptor antagonists and their therapeutic potential.”Expert Opin. Ther. Patents, 2008, 18, 2: 123-142. Yet some proffer thatglutamate analogs targeting the orthosteric binding site may be limitedby low brain penetration and insufficient selectivity with respect tothe different mGluRs subtypes. Synthetic agonists may lead to continuousstimulation of the receptor since they are often designed to bemetabolically stable. This continuous stimulation is not necessarilydesirable, due to potential receptor desensitization issues. Also, withrespect to receptor occupancy, synthetic antagonists may lead toprolonged blockade of receptor function, which may not be compatiblewith the kinetics of the pathology of a central nervous system disorder.

However, a more selective and controlled “fine-tuning” action on themGlu5 receptor is feasible through allosteric modulation. See e.g., P.Bach et al., “Metabotropic glutamate receptor 5 modulators and theirpotential therapeutic applications,” Expert Opin. Ther. Patents., 2007,17, 4: 371-381. Allosteric modulation refers to binding by a modulatorligand to a site on a receptor that is different from the orthostericprimary substrate or ligand binding site. This ligand binding processresults in conformational changes, which may profoundly influence thefunction of the protein (e.g., G protein-coupled receptors such asmGluRs, including mGluR5). Novel mGluR5 ligands that allostericallymodulate the mGlu5 receptor may improve the therapeutic window oftraditional central nervous system agents and/or the treatment ofcentral nervous system disorders. The present invention is directedthese, and other important, ends.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I):

wherein:

-   -   R¹ and R² are each independently alkyl, cycloalkyl,        ketocycloalkyl, heterocyclyl, aryl or heteroaryl, which is        optionally mono-, di-, or tri-substituted independently with        alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino,        alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl,        heterocyclyl-R³, —NHR³, —N(alkyl)R³, —C(O)NHR³, —C(O)N(alkyl)R³,        —NHC(O)R³, —N(alkyl)C(O)R³, —OH or —OR³, wherein:        -   R³ is C₁-C₆alkyl or C₁-C₆cycloalkyl, which is optionally            substituted with halogen, C₁-C₃alkoxy, OH, —CN,            —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, C₁₋₃alkylheterocyclyl,            C₁-C₃alkylcarbamate, —C(O)NH(C₁-C₃alkyl),            —C(O)N(C₁-C₃alkyl)₂, —NHC(O)—C₁-C₃alkyl,            —N(C₁-C₃alkyl)-C(O)—C₁-C₃alkyl, OH, or —O—C₁-C₆alkyl;            with the proviso that the compound of formula (I) is not:

-   N,N′-(1,3-admantylene)bis(3-methoxy-benzamide);

-   N,N′-(1,3-adamantylene)bis(4-ethoxy-benzamide);

-   N,N′-(1,3-adamantylene)bis(4-methoxy-benzamide);

-   N,N′-(1,3-adamantylene)bis(3,4,5-trimethoxybenzamide);

-   N,N′-(1,3-adamantylene)bis(2-iodo-benzamide);

-   N,N′-(1,3-adamantylene)bis-benzamide;

-   N,N′-(1,3-adamantylene)bis(3-nitrobenzamide); and

-   N,N′-(1,3-adamantylene)bis-(3-pyridinecarboxamide); or    a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical compositioncomprising at least one compound of the invention or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present invention also provides a method of treating a disease ordisorder, the method comprises administering a therapeutically effectiveamount of at least one compound of the present invention or apharmaceutically acceptable salt thereof to a mammal in need thereof,wherein the disease or disorder is a central nervous system disease ordisorder. In some embodiments of the method, a symptom of the disease ordisorder is treated.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides adamantyl diamidederivatives. The present invention comprises a compound of formula (I):

wherein:

-   -   R¹ and R² are each independently alkyl, cycloalkyl,        ketocycloalkyl, heterocyclyl, aryl or heteroaryl, which is        optionally mono-, di-, or tri-substituted-independently with        alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino,        alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl,        heterocyclyl-R³, —NHR³, —N(alkyl)R³, —C(O)NHR³, —C(O)N(alkyl)R³,        —NHC(O)R³, —N(alkyl)C(O)R³, —OH or —OR³, wherein:        -   R³ is C₁-C₆alkyl or C₁-C₆cycloalkyl, which is optionally            substituted with halogen, C₁-C₃alkoxy, OH, —CN, —NH₂,            —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, C₁-C₃alkylheterocyclyl,            C₁-C₃alkylcarbamate, —C(O)NH(C₁-C₃alkyl),            —C(O)N(C₁-C₃alkyl)₂, —NHC(O)—C₁-C₃alkyl,            —N(C₁-C₃alkyl)-C(O)═C₁-C₃alkyl, OH, oe —O—C₁-C₆alkyl;            with the proviso that the compound of formula (I) is not:

-   N, N′-(1,3-adamantylene)bis(3-methoxy-benzamide) (i.e., the compound    having CAS registry number 899289-36-2);

-   N,N′-(1,3-adamantylene)bis(4-ethoxy-benzamide) (i.e., the compound    having CAS registry number 899289-24-8);

-   N,N′-(1,3-adamantylene)bis(4-methoxy-benzamide) (i.e., the compound    having CAS registry number 899259-96-2);

-   N,N′-(1,3-adamantylene)bis(3,4,5-trimethoxybenzamide) (i.e., the    compound having CAS registry number 173068-46-7);

-   N,N′-(1,3-adamantylene)bis(2-iodo-benzamide) (i.e., the compound    having CAS registry number 899259-92-8);

-   N,N′-(1,3-adamantylene)bis-benzamide (i.e., the compound having CAS    registry number 103307-81-9);

-   N,N′-(1,3-adamantylene)bis(3-nitrobenzamide) (i.e. the compound    having CAS registry number 350024-39-4); and

-   N,N′-(1,3-adamantylene)bis-(3-pyridinecarboxamide) (i.e., the    compound having CAS registry number 371933-95-8); or    -   a pharmaceutically acceptable salt thereof.

The term “alkyl”, employed alone or as part of a group, is definedherein, unless otherwise stated, as either a straight-chain or branchedsaturated hydrocarbon of 1 to 8 carbon atoms. In some embodiments, thealkyl moiety contains 8, 7, 6, 5, 4, 3, 2 or 1 carbon atoms. Where theterm “alkyl” appears herein without a carbon atom range it means a rangeof C₁-C₈. Examples of saturated hydrocarbon alkyl moieties include, butare not limited to, chemical groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl,and the like.

The term “alkoxy”, employed alone or in combination with other terms, isdefined herein, unless otherwise stated, as —O-alkyl, where “alkyl” isas previously defined herein. Examples of alkoxy moieties include, butare not limited to, chemical groups such as methoxy, ethoxy,iso-propoxy, sec-butoxy, tert-butoxy, and homologs, isomers, and thelike. Alkoxy also refers to —O-alkyl moieties where the alkyl group issubstituted by hydroxy, cyano, alkoxy, alkylamino, dialkylamino,alkylamide, dialkylamide, and the like, including without limitation,—OC₁-C₄alkyl-OH, —OC₁-C₄alkyl-OCH₃, —OC₁-C₄alkyl-NHCH₃,—OC₁-C₄alkyl-N(CH₃)₂, —OC₁-C₄alkyl-CONHCH₃, —OC₁-C₄alkyl-CON(CH₃)₂,—OC₁-C₄alkyl-NHCOCH₃, and —OC₁-C₄alkyl-N(CH₃)COCH₃.

As used herein, the term “cycloalkyl”, employed alone or in combinationwith other terms, is defined herein, unless otherwise stated, as acyclized alkyl group having from 3 to 8 ring carbon atoms, where “alkyl”is as defined herein. Examples of cycloalkyl moieties include, but arenot limited to, chemical groups such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

As used herein, the term “ketocycloalkyl”, employed alone or incombination with other terms, is defined herein, unless otherwisestated, as a cycloalkyl having a keto radical attached thereto, where“cycloalkyl” is as defined herein. Examples include cyclopentanone orcyclohexanone.

The terms “halo” or “halogen”, employed alone or in combination withother terms, is defined herein, unless otherwise stated, as fluoro,chloro, bromo, or iodo.

The term “aryl”, employed alone or in combination with other terms, isdefined herein, unless otherwise stated, as an aromatic hydrocarbon ofup to 14 carbon atoms, which can be a single ring (monocyclic) ormultiple rings (e.g., bicyclic, tricyclic, polycyclic) fused together orlinked covalently. Any suitable ring position of the aryl moiety can becovalently linked to the defined chemical structure. Examples of arylmoieties include, but are not limited to, chemical groups such asphenyl, benzyl, 1-naphthyl, 2-naphthyl, and the like. An aryl group canbe unsubstituted or substituted as described herein.

The term “heteroaryl” employed alone or in combination with other terms,is defined herein, unless otherwise stated, as a monocyclic orpolycyclic (fused together or linked covalently) aromatic hydrocarbonring comprising one or more heteroatoms independently selected fromnitrogen, oxygen, and sulfur. A heteroaryl group comprises up to 14carbon atoms and 1 to 6 heteroatoms. Examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, triazinyl,pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl,pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl,thiazolyl, oxazolyl, 2-quinolinyl, 2-quinazolinyl, 3-phenyl-2-quinolinyland the like. A heteroaryl group can be unsubstituted or substituted asdescribed herein.

The term “heterocyclyl” employed alone or in combination with otherterms, is defined herein, unless otherwise stated, as a univalent groupformed by removing a hydrogen atom from any ring atom of a heterocycle.

The term “acyl” employed alone or in combination with other terms, isdefined herein, unless otherwise stated, as groups of formula—C(O)-alkyl, where alkyl is a previously described herein; i.e., analkylcarbonyl, such as formyl, acetyl and the like.

The term “aminoalkyl” employed alone or in combination with other terms,is defined herein, unless otherwise stated, as alkyl-amino, where theterm “alkyl” is as previously defined herein and the term “amino” is—NH₂, —NH—, or —N<. Non-limiting examples include —CH₃NH—, CH₃CH₂NH—,(C₁-C₃alkyl)NH—, (C₁-C₃alkyl)₂N—, and the like.

The term “alkylamino” employed alone or in combination with other terms,is defined herein, unless otherwise stated, as amino-alkyl, where theterm “alkyl” is as previously defined herein and the term “amino” is—NH₂, —NH—, or —N<. Non-limiting examples include —NHCH₃, —NHCH₂CH₃,—NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, and the like.

In some embodiments of the invention, R¹ and R² are both aryl. In someembodiments, R¹ and R² are both heteroaryl. In some embodiments, R¹ isaryl and R² is heteroaryl. In some embodiments of the invention, atleast one aryl is phenyl. In some embodiments, at least one heteroarylis pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, pyrazolyl, indazolyl,thiophenyl, furanyl, or benzofuranyl. In some embodiments, both arylsare phenyl. In some embodiments, both heteroaryls are selected from agroup consisting of pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl,pyrazolyl, indazolyl, thiophenyl, furanyl, and benzofuranyl.

In some embodiments of the invention, at least one aryl or heteroaryl issubstituted as previously described. In some such embodiments, the 1, 2,or 3 substituents are independently selected from the group consistingof methyl, methoxy, dimethylamino-ethoxy, amino, methylamino,dimethylamino, cyano, chloro, fluoro, furanyl and thiophenyl.

In some embodiments, R¹ and R² each are independently selected from agroup consisting of phenyl, 3 or 4-methyl-phenyl, 3 or 4-chloro-phenyl,3 or 4-fluoro-phenyl, 3 or 4-dimethylamino-ethoxy-phenyl, 3 or4-dimethylamino-phenyl, 3 or 4-cyano-phenyl,3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl, 1H-indole-5-yl,1H-indole-6-yl, 1H-benzimidazole-5-yl, pyridyl, 2-pyridyl, 4-pyridyl, 4-or 5-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl, 6-chloro-pyridin-2-yl,pyrazin-2-yl, thiazol-2-yl, 5-(thiophen-2-yl)-1H-pyrazol-3-yl,1-methyl-5-(thiophen-2-yl)-1H-pyrazol-3-yl,5-(furan-2-yl)-1-methyl-1H-pyrazol-3-yl, indazol-3-yl,2-methyl-2H-indazol-3-yl, benzofuranyl, benzofuran-5-yl.

In some embodiments, the compound of the present invention is a compounddisclosed in the Experimental Section below. In some embodiments, thecompound is one from Table 1, 2, 3, or 4, below.

In some embodiments of the invention, R¹ and R² are both aryl. In someembodiments, R¹ and R² are both heteroaryl. In some embodiments, R¹ isaryl and R² is heteroaryl. In some embodiments, either R¹ or R² isheteroaryl. In some embodiments, either R¹ or R² is aryl.

In some embodiments of the invention, at least one aryl is phenyl. Insome embodiments, at least one heteroaryl is benzofuranyl,benzo[c]isoxazolyl, benzooxazolyl, benzothiazolyl,dihydrothieno[3,4-b][1,4]dioxinyl, furanyl, imidazo[1,2-a]pyridinyl,indazolyl, indolinyl, indolyl, isoquinolinyl, isoxazolyl,naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolo[3,2-e]pyridine, quinolinyl, quinoxalinyl,thiazolyl, or thiophenyl.

In some embodiments, both aryls are phenyl. In some embodiments, bothheteroaryls are selected from a group consisting of at least oneheteroaryl is benzofuranyl, benzo[c]isoxazolyl, benzoxazolyl,benzothiazolyl, dihydrothieno[3,4-b][1,4]dioxinyl, furanyl,imidazo[1,2-a]pyridinyl, indazolyl, indolinyl, indolyl, isoquinolinyl,isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolo[3,2-c]pyridinyl, quinolinyl,quinoxalinyl, thiazolyl, or thiophenyl.

In some embodiments, the heteroaryl is pyridinyl, and the pyridinyl ismono-, di-, or tri-substituted as previously defined. In some suchembodiments, the mono-, di-, or tri-substitutions are independentlyheteroaryl, heterocyclyl, heterocyclyl-R³, —N(alkyl)R³, wherein R³ is aspreviously defined.

In some embodiments of the invention, R¹ is aryl or heteroaryl and R² iscycloalkyl, ketocycloalkyl or heterocyclyl. In some embodiments, eitherR¹ or R² is cycloalkyl. In some embodiments, at least one cycloalkyl iscyclobutyl, cyclohexyl, cyclopentyl, or cyclopropyl. In someembodiments, the cycloalkyl is further substituted beyond thetri-substitution previously defined, i.e., the cycloalkyl is substitutedmore than three times as previously described; for example, thecycloalkyl is tetra-substituted with fluorine.

In some embodiments of the invention, at least one cycloalkyl,ketocycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted aspreviously described. In some such embodiments, the 1, 2, or 3substituents are independently selected from the group consisting ofmethyl, methoxy, dimethylamino-ethoxy, amino, methylamino,dimethylamino, cyano, chloro, fluoro, furanyl and thiophenyl.

In some embodiments, the mono-, di-, or tri-substituents areindependently selected from the group consisting of amino, chloro,cyano, dimethylamino, dimethylamino-ethoxy, methyl, methylamino,methoxy, fluoro, —C(O)NHCH₃, furanyl, pyrrolidinyl, thiophenyl andtrifluoromethyl.

In some embodiments, the compound of the present invention is a compounddisclosed in the Experimental Section below. In some embodiments, thecompound is one from Table 1, Table 2, Table 3 or Table 4, below.

Another aspect of the present invention is a composition that comprisesa pharmaceutically effective amount of a compound according to thepresent invention, and a pharmaceutically acceptable carrier orexcipient.

A composition of the present invention may be adapted to any mode ofadministration, such as orally (including sublingually), via implants,parentally (including intravenous, intraperitoneal, intraarticularly andsubcutaneous injections), rectally, intranasally, topically, ocularly(via eye drops), vaginally, and transdermally.

A compound of the present invention can be used either as a free base orin the form of a salt derived from pharmaceutically acceptable acids orbases. The salt, includes without limitation the following: salts withinorganic acids, e.g., hydrochloric acid, hydrobromie acid, sulfuricacid, nitric acid, and phosphoric acid, and organic acids e.g., aceticacid, oxalic acid, citric acid, tartaric acid, succinic acid, maleicacid, benzoic acid, benzene sulfonic acid, fumaric acid, malic acid,methane sulfonic acid, pamoic acid, and para-toluene sulfonic acid.Other salts include salts with alkali metals or alkaline earth metals,e.g., sodium, potassium, calcium and magnesium, or with organic bases,including quaternary ammonium salts. Further non-limiting examples ofpharmaceutically acceptable inorganic and organic acid addition saltsinclude those listed in [S. M. Berge et al., J. Pharm. Sci. 1977, 66, 1:2, and G. S. Paulekuhn, et al., J. Med. Chem. 2007, 50, 26: 6665-6672].

A compound of the present invention can also be used in the form of anester, carbamate and other conventional prodrug form, which generallywill be a functional derivative of the compound that is readilyconverted to the active moiety in vivo. Also included are metabolites ofa compound of the present invention defined as active species producedupon introduction of the compound into a biological system.

When a compound of the present invention is employed as described above,it may be combined with one or more pharmaceutically acceptableexcipients or carriers, e.g., solvents, diluents and the like. Suchpharmaceutical preparations may be administered orally in such forms astablets, capsules (including, e.g., time release and sustained releaseformulations), pills, lozenges, aerosols, dispersible powders, granules,solutions, suspensions (containing, e.g., a suspending agent, at, e.g.,from about 0.05 to about 5% of suspending agent), syrups (containing,e.g., sugar or a sugar substitute such as aspartame, at, e.g., about 10to about 50% sugar or sugar substitute), elixirs and the like, orparenterally in the form of sterile injectable solutions, suspensions oremulsions containing, e.g., from about 0.05 to about 5% suspending agentin an isotonic medium. Such preparations may contain, e.g., from about25 to about 90% of the active ingredient in combination with thecarrier, more customarily from about 5% and about 60% by weight. Theeffective dosage of an active ingredient (e.g., a compound or salt ofthe present invention and a prodrug or metabolite thereof) employed mayvary depending on the particular compound, salt, prodrug or metaboliteused, the mode of administration, age, weight, sex and medical conditionof the patient, and the severity of the disease, disorder, condition,and/or system being treated. The selection of the appropriateadministration and dosage form for an individual mammal will be apparentto those skilled in the art. Such determinations are routine to aphysician, veterinarian or clinician of ordinary skill in the art (seee.g., Harrison's. Principles of Internal Medicine, Anthony Fauci et al.(eds.) 14^(th) ed. New York: McGraw Hill (1998)). Further, the dosageregimen may be adjusted to provide the optimal therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the needs of the therapeuticsituation.

Solid carriers, e.g., starch, lactose, dicalcium phosphate,microcrystalline cellulose, sucrose and kaolin, liquid carriers, e.g.,sterile water, polyethylene glycols, glycerol, non-ionic surfactants andedible oils such as corn, peanut and sesame oils, may be employed as areappropriate to the nature of the active ingredient and the particularform of administration desired. Adjuvants customarily employed in thepreparation of pharmaceutical compositions may be advantageouslyincluded. Non-limiting examples of adjuvants include flavoring agents,coloring agents, preserving agents, and antioxidants, such as vitamin E,ascorbic acid, BHT and BHA.

An active compound also may be administered parenterally orintraperitoneally. Solutions or suspensions of the active compound as afree base, neutral compound or pharmacologically acceptable salt can beprepared in water suitably mixed with a surfactant such ashydroxypropylcellulose. Dispersions also can be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Thesepreparations may contain a preservative to prevent the growth ofmicroorganisms under ordinary conditions of storage and use.

The pharmaceutical forms suitable for injectable or infusing use includesterile aqueous solutions, suspensions or dispersions, and sterilepowders for the extemporaneous preparation of sterile injectable orinfusing solutions, suspension or dispersions. In all cases, the formmust be sterile and must be fluid to the extent that easy injectabilityand infusing exists. It must be stable under conditions of manufactureand storage and must be preserved against the contaminating action ofmicroorganisms. The carrier can be a solvent or dispersion mediumcontaining, for example, water, ethanol, and polyol (e.g., glycerol,propylene glycol, and liquid polyethylene glycol), suitable mixturesthereof, and vegetable oil.

Furthermore, active compounds of the present invention can beadministered intranasally or transdermally using vehicles suitable forintranasal or transdermal delivery known to those ordinarily skilled inthe art. Transdermal administration includes all administrations acrossthe surface of the body and the inner linings of bodily passagesincluding epithelial and mucosal tissues, using carrier systems such aslotions, creams, foams, pastes, patches, suspensions, solutions, andsuppositories (rectal and vaginal). Creams and ointments may be viscousliquid or semisolid emulsions of either the oil-in-water or water-in-oiltype. Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the active ingredient also may besuitable. A variety of occlusive devices may be used to release theactive ingredient into the blood stream such as a semi-permeablemembrane covering a reservoir containing the active ingredient with orwithout a carrier, or a matrix containing the active ingredient. Otherocclusive devices are known in the literature. When using a transdermaldelivery system, the dosage administration will be continuous ratherthan a single or divided daily dose.

A compound of the present invention can also be administered in the formof a liposome delivery system where the liposomal lipid bilayer isformed from a variety of phospholipids. A compound of the presentinvention also may be delivered by the use of a carrier such asmonoclonal antibodies to which the compound is coupled. Other carriersto which a compound of the present invention also may be coupled are asoluble polymer or a biodegradable polymer useful in achievingcontrolled release of an active ingredient.

It is understood by those practicing the art that some of the compoundsof the present invention may contain one or more asymmetric centers, andthus may give rise to enantiomers and diastereomers. The presentinvention includes all stereoisomers including individual diastereomersand resolved, enantiomerically pure stereoisomers, as well as racemates,and all other variations of stereoisomers, and mixtures andpharmaceutically acceptable salts thereof, which possess the indicatedactivity. Optical isomers may be obtained in pure form by customaryprocedures known to those skilled in the art, and include, but are notlimited to, chiral chromatographic separations, diastereomeric saltformation, kinetic resolution, and asymmetric synthesis. It is alsounderstood that this invention encompasses all possible regioisomers,endo-exo isomers, and mixtures thereof that possess the indicatedactivity. Such isomers can be obtained in pure form by customaryprocedures known to those skilled in the art, and include, but are notlimited to, column chromatography, thin-layer chromatography, andhigh-performance liquid chromatography. It is understood by thosepracticing the art that some of the compounds of the present inventionmay be chiral due to hindered rotation, and give rise to atropisomers,which can be resolved and obtained in pure form by customary proceduresknown to those skilled in the art. It is further understood by thosepracticing the art that some of the compounds of the present inventioninclude structural isomers, including tautomers.

Included also in this invention are all polymorphs and hydrates, of thecompounds of the present invention.

Another aspect of the present invention is a method for using thecompounds of the invention. The invention is to be understood asembracing all simultaneous, sequential or separate use of anycombination of the compounds of the invention with any pharmaceuticalcomposition useful in the methods described herein.

In some embodiments, the method includes administering an effectiveamount of a combination of two or more of the compounds describedherein, or salts thereof. It is specifically intended that the phrases“combination of two or more of the compounds described herein, or saltsthereof,” or “at least one compound as described herein, or apharmaceutically acceptable salt thereof,” or similar languagedescribing specific compounds, includes the administration of suchcompounds in any proportion and combination of salt, neutral or freebase forms; i.e., includes the administration of such compounds each inthe base form, each in the neutral form or each in the salt form, or oneor more in the base form and one or more in the neutral form, or one ormore in the base form and one or more in the salt form, or one or morein the neutral form and one or more in the salt form, in any proportionof the neutral and/or basic compounds and/or salts.

As used herein, the phrase “effective amount” when applied to a compoundof the invention, is intended to denote an amount sufficient to cause anintended biological effect. The phrase “therapeutically effectiveamount” when applied to a compound of the invention is intended todenote an amount of the compound that is sufficient to ameliorate,palliate, stabilize, reverse, slow or delay the progression of adisorder or disease state, or of a symptom of the disorder or disease.In some embodiments, the method of the present invention provides foradministration of combinations of compounds. In such instances, the“effective amount” is the amount of the combination sufficient to causethe intended biological effect.

The term “treatment” or “treating” as used herein means curing,ameliorating or reversing the progress of a disease or disorder, orameliorating or reversing one or more symptoms or side effects of suchdisease or disorder. “Treatment” or “treating”, as used herein, alsomeans to inhibit or block, as in retard, arrest, restrain, impede orobstruct, the progress of a system, condition or state of a disease ordisorder. For purposes of this invention, “treatment” or “treating”further means an approach for obtaining beneficial or desired clinicalresults, where “beneficial or desired clinical results” include, withoutlimitation, alleviation of a symptom, diminishment of the extent of adisorder or disease, stabilized (i.e., not worsening) disease ordisorder state, delay or slowing of a disease or disorder state,amelioration or palliation of a disease or disorder state, and remissionof a disease or disorder, whether partial or total, detectable orundetectable.

The term “prevent” or “preventing” as used herein means to keep fromhappening or existing. The term “administering” as used herein refers toeither directly administering a compound of the present invention, oradministering a prodrug, derivative, or analog of same, that will forman effective amount of the compound within a mammal.

The present invention also provides a method of treating a disease ordisorder, the method comprises administering a therapeutically effectiveamount of at least one compound of the present invention or apharmaceutically acceptable salt thereof to a mammal in need thereof,wherein the disease or disorder is a central nervous system disease ordisorder.

A compound of the present invention can allosterically modulate themGlu5 receptor. An allosteric modulator that enhances or potentiates theaffinity of an orthosteric ligand for the mGluR5 receptor and/orenhances or potentiates an orthosteric agonist's efficacy is anallosteric enhancer (or potentiator) or positive allosteric modulator(PAM). See e.g., May, L. T. Annu. Rev. Pharmacol. Toxicol. 2007, 47,1-51. An allosteric modulator that reduces or diminishes the affinity ofan orthosteric ligand for the mGluR5 receptor and/or reduces ordiminishes an orthosteric agonist's efficacy is an allosteric antagonist(or inhibitor) or negative allosteric modulator (NAM). Id.

In some embodiments, the mammal of the method of the invention is ahuman.

In some embodiments of the method of the invention, the central nervoussystem disease or disorder is a cognitive, neurodegenerative,psychiatric or neurological disease or disorder. In some suchembodiments, the cognitive, neurodegenerative, psychiatric orneurological disease or disorder is selected from a group consisting ofa mood disorder, an anxiety, a schizophrenia (including schizoaffectivedisorders), Alzheiiner's disease, Parkinson's disease, multiplesclerosis, Huntington's chorea, amyotrophic lateral sclerosis,Creutzfeld-Jakob disease, a trauma-induced neurodegeneration,AIDS-induced encephalopathy, another infection-related encephalopathy(i.e., a non-AIDS-induced encephalopathy), Fragile X syndrome, an autismspectrum disorder, and a combination thereof.

As used herein, the phrase “mood disorder” refers to any of severalpsychological disorders characterized by abnormalities of emotionalstate, such as, without limitation, bipolar disorders, depressivedisorders, cyclothymic disorders, dysthymic disorders, mood disordersdue to a general medical condition, mood disorders not otherwisespecified and substance-induced mood disorders; and as characterized bythe Diagnostic and Statistical Manual of Mental Disorders, FourthEdition (DSM-IV) (American Psychiatric Association: Arlington, Va.,1994).

As used herein, the phrase “autism spectrum disorder” (ASD) refers to adisorder that causes severe and pervasive impairment in thinking,feeling, language, and the ability to relate to others, which is oftenfirst diagnosed in early childhood and range from a severe form, calledautistic disorder (“classic” autism), through pervasive developmentdisorder not otherwise specified (PDD-NOS), to a much milder form,Asperger syndrome. The phrase, as used herein, also includes Rettsyndrome and childhood disintegrative disorder, and as used herein, issynonymous with the phrase, “pervasive developmental disorders” (PDDs).

In some such embodiments, the mood disorder is a depression (i.e., adepressive disorder). In some such embodiments, the depression isselected from the group consisting of atypical depression, bipolardepression, unipolar depression, major depression, endogenous depression(i.e., acute depression with no obvious cause), involutional depression(i.e., depression that occurs in mid-life or the elderly), reactivedepression (i.e., depression caused by an obvious traumatic lifeepisode), postpartum depression, primary depression (i.e., depressionthat has no obvious physical or psychological cause such as a medicalillness or disorder), psychotic depression, and secondary depression(i.e., depression that seems to be caused by some other underlyingcondition such another medical illness or disorder).

In some such embodiments, the anxiety disease or disorder is selectedfrom a group comprising generalized anxiety disorder, panic anxiety,obsessive compulsive disorder, social phobia, performance anxiety,post-traumatic stress disorder, acute stress reaction, an adjustmentdisorder, a hypochondriacal disorder, separation anxiety disorder,agoraphobia, a specific phobia, anxiety disorder due to general medicalcondition, substance-induced anxiety disorder, alcoholwithdrawal-induced anxiety, and a combination thereof.

In some embodiments, the central nervous system disease or disorder ofthe method of the invention is a seizure disease or disorder. In someembodiments, the seizure disease or disorder is selected from the groupconsisting of a convulsion epilepsy, status epilepticus, and acombination thereof.

In some embodiments, the central nervous system disease or disorder ofthe method of the invention is a pain disease or disorder selected fromthe group consisting of inflammatory pain, neuropathic pain and migrainepain. In some embodiments, the neuropathic pain or migraine pain diseaseor disorder is selected from the group consisting of allodynia,hyperalgesic pain, phantom pain, neuropathic pain related to diabeticneuropathy, neuropathic pain related to migraine, and a combinationthereof.

In some embodiments, the central nervous system disease or disorder ofthe method of the invention is a neuronal hyperexcitation state diseaseor disorder. In some embodiments, the neuronal hyperexcitation statedisease or disorder is a neuronal hyperexcitation state in medicamentwithdrawal, a neuronal hyperexcitation state in intoxication, or acombination thereof.

In some embodiments of the method of the invention, at least one symptomof the cognitive neurodegenerative, psychiatric or neurological diseaseor disorder is treated.

In some embodiments, the cognitive, neurodegenerative, psychiatric orneurological disease or disorder is a depression. In some suchembodiments, the at least one symptom of the depression is depressedfeeling, depressed mood, loss of interest or pleasure in some or allactivities, changes in appetite, changes in weight, changes in sleeppatterns, lack of energy, fatigue, low self esteem, diminished capacityfor thinking, concentration, or decisiveness, feelings of hopelessnessor worthlessness, psychomotor agitation or retardation, self-reproach,inappropriate guilt, frequent thoughts of death or suicide, plans orattempts to commit suicide, or a combination thereof.

In some embodiments, the cognitive, neurodegenerative, psychiatric orneurological disease or disorder is an anxiety. In some suchembodiments, the at least one symptom of anxiety is apprehension, fear,trembling, muscle aches, insomnia, abdominal upsets, dizziness,irritability, persistent, recurring thoughts, compulsions, heartpalpitations, chest pain, chest discomfort, sweating, tinglingsensations, feeling of choking, fear of losing control, flashbacks,nightmares, intrusive thoughts, intrusive recollections, avoidancebehaviors, emotional numbing, an inability to sleep, anxious feelings,overactive startle response, hypervigilance, outbursts of anger,faintness, blushing, profuse sweating, or a combination thereof.

In some embodiments, the cognitive, neurodegenerative, psychiatric orneurological disease or disorder is schizophrenia. In some suchembodiments, the at least one symptom of schizophrenia is a positivesymptom selected from the group consisting of hallucination, delusion,paranoia, and a combination thereof. In some such embodiments, thesymptom of schizophrenia is a negative symptom selected from the groupconsisting of social withdrawal, flat affect, anhedonia, decreasedmotivation, and a combination thereof. In some such embodiments, thesymptom of schizophrenia is a cognitive symptom selected from the groupconsisting of severe deficit in attention, severe deficit in objectnaming, severe deficit in working memory, severe deficit in long-termmemory storage, severe deficit in executive functioning, a slowing ofinformation processing, a slowing of neural activity, long termdepression, and a combination thereof.

In some embodiments of the method of the invention, the cognitive,neurodegenerative, psychiatric or neurological disease or disorder isParkinson's disease. In some such embodiments, the at least one symptomof Parkinson's disease is levodopa-induced dyskinesia, poor balance,Parkinsonian gait, bradykinesia, rigidity, tremor, change in speech,loss of facial expression, micrographia, difficulty swallowing,drooling, pain, dementia, confusion, a sleep disturbance, constipation,a skin problem, depression, fear, anxiety, difficulty with memory,slowed thinking, sexual dysfunction, an urinary problem, fatigue,aching, loss of energy, or a combination thereof.

In some embodiments, the cognitive, neurodegenerative, psychiatric orneurological disease or disorder is Alzheimer's disease. In some suchembodiments, the at least one symptom of Alzheimer's disease isimpairment in memory, impairment in attention, impairment in judgment,impairment in decision-making, impairment in orientation to physicalsurroundings, language impairment, impairment in speed-dependentactivities, impairment in abstract reasoning, impairment in visuospatialabilities, impairment in executive functioning, impairment in behavioraldisturbances, disinterest and passivity, apathy, inappropriate dressing,poor self care, agitation, violent outburst, aggression, depression,anxiety, hallucination, delusion, change in personality, change in mood,dementia, or a combination thereof.

In some embodiments, the cognitive, neurodegenerative, psychiatric orneurological disease or disorder is multiple sclerosis. In some suchembodiments, the at least one symptom of multiple sclerosis is opticneuritis blurred vision, eye pain, loss of color vision, blindness,diplopia double vision, nystagmus jerky eye movements, ocular dysmetria,constant under- or overshooting eye movements, internuclearophthalmoplegia, nystagmus, diplopia, movement and sound phosphenes,diplopia, afferent pupillary defect, motor paresis, monoparesis,paraparesis, hemiparesis, quadraparesis plegia, paraplegia, hemiplegia,tetraplegia, quadraplegia, spasticity, dysarthria, muscle atrophy,spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless legsyndrome, footdrop dysfunctional reflexes (MRSs, Babinski's, Hoffman's,Chaddock's), paraesthesia, anaesthesia, neuralgia, neuropathic pain,neurogenic pain, l′ hermitte's, proprioceptive dysfunction, trigeminalneuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia,vertigo, speech ataxia, dystonia, dysdiadochokinesia, frequentmicturation, bladder spasticity, flaccid bladder, detrusor-sphincterdyssynergia, erectile dysfunction, anorgasmy, retrograde ejaculation,frigidity, constipation, fecal urgency, depression, cognitivedysfunction, dementia, mood swings, emotional lability, euphoria,bipolar syndrome, anxiety, aphasia, dysphasia, fatigue, uhthoffssymptom, gastroesophageal reflux, a sleeping disorder, or a combinationthereof.

The present invention further provides a method of treatinggastroesophageal reflux, the method comprises administering atherapeutically effective amount of at least one compound of claim 1 ora pharmaceutically acceptable salt thereof to a mammal in need thereof.

The present invention further provides a method of treating alcoholdependence, the method comprises administering a therapeuticallyeffective amount of at least one compound of claim 1 or apharmaceutically acceptable salt thereof to a mammal in need thereof.

In some embodiments, the compound of the present invention is used inthe preparation of a medicament for treatment of a central nervoussystem disease or disorder. In some embodiments, the central nervousdisease or disorder is as previously disclosed herein.

Another aspect of the present invention is a process for producing thecompounds of the present invention.

Preparation of the Compounds of the Present Invention

The compounds of the present invention may be prepared, withoutlimitation, according to one of the general methods outlined below. Forexample, Schemes 1-11 that follow are intended as an illustration ofsome embodiments of the invention and no limitation of the presentinvention is implied because of them.

The following defines acronyms as used herein unless specified otherwisein a particular instance.

BOP=benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate, CAS No. 56602-33-6DCM=dichloromethane or methylene chloride

DIEA=N,N-diisopropylethylamine, CAS No. 7087-68-5DMA=N,N-dimethylacetamide, CAS No. 127-19-5

DMC=dimethylimidazolinium chloride

DMF=N,N-dimethylformamide, CAS No. 68-12-2

DPPA=Diphenylphosphoryl azide, CAS No. 26386-88-9EDCI N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride, CASNo. 93128-40-6HBTU=2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluroniumhexafluorophosphate, CAS No. 94790-37-1

NMP=N-Methyl-Pyrrolidone, CAS No. 872-50-4

P PyBOP=benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate, CAS No. 128625-52-5RT or rt=room temperatureTBTU=O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate, CAS No. 125700-67-6TEA=triethanolamine, CAS No. 102-71-6THF=tetrahydrofuran, CAS No. 109-99-9

Symmetrical amides of the formula (I) (R¹═R²) can be prepared via theprocess outlined in Scheme 1 using customary amidation procedures fromcommercially available compound 1, adamantane-1,3-diamine, where R¹ isequal to R², and R¹ and R² are as previously defined herein.

Unsymmetrical amides of formula (I) (R¹≠R²) also can be prepared via theprocesses outlined in Schemes 2 and 3, where R¹ and R² are as previouslydefined herein.

Amidation of compound 1 with a mixture of R¹COCl and R²COCl, or amixture of R¹CO₂H and R²CO₂H using customary amidation proceduresaffords unsymmetrical amides of formula (I).

Amidation of Intermediate A with R²CO₂H or R²COCl using customaryamidation procedures affords unsymmetrical amides of formula (I).

Intermediate A can be prepared via the processes outlined in Schemes4-6.

Amidation of compound 1 with R¹CO₂H or R¹COCl using customary amidationprocedures yields Intermediate A. The yield of this route is low due tothe formation of bis-amides.

Commercially available 1-adamantanecarboxylic acid (compound 2) can beconverted to acetamide 3 via a Ritter reaction. Hydrolysis of compound 3under acidic conditions affords the corresponding amine salt, which isthen converted to methyl ester 4. Customary amidation of compound 4affords compound 5. Hydrolysis of ester 5 followed by a standard Curtiusrearrangement yields Intermediate A.

Customary amidation of commercially available 3-amino-adamantan-1-ol(compound 6) affords monoamide 7, which is then converted to compound 8via a Ritter reaction. Hydrolysis of compound 8 affords Intermediate A.

Amides with solubilizing, groups (formula I-A, I-B and I-C) can beprepared via the processes outlined in Schemes 7-9.

Displacement of chloride of Intermediate B with amines)(R²⁰)NH(R²¹)under basic conditions with microwave irradiation yields compounds offormula (I-A), where R²⁰ and R²¹ are alkyl or linked together to form aheterocycle that is optionally substituted by hydroxyl, alkoxy, amine,alkylamine, dialkylamine, —C(O)NH-alkyl, —C(O)N(dialkyl), —NHC(O)-alkyl,—N(alkyl)-C(O)-alkyl; or one of R²⁰ and R²¹ is H and the other is alkyl,cycloalkyl or heterocycle that is optionally substituted by hydroxyl,cyano, alkoxy, amine, alkylamine, dialkylamine, —C(O)—NH₂,—C(O)NH-alkyl, —C(O)N(dialkyl), —NHC(O)-alkyl, —N(alkyl)-C(O)-alkyl; Q,Y and W are CR²³, where R²³ is H, alkyl or cycloalkyl; or one of Q, Yand W is nitrogen.

Alkylation of commercially available compound 9 with R²⁴Br, R²⁴OMs orR²⁴OTs under basic conditions such as K₂CO₃ or Cs₂CO₃ in DMF affordscompound 10. R²⁴OMs or R²⁴OTs could be easily made from correspondingR²⁴OH and MeSO₂Cl or 4-methylbenzenesulfonyl chloride. Saponification ofester 10 gives carboxylic acid 11. Amidation of compound 11 withIntermediate A using customary procedures could yield compounds offormula (I-B), where R²⁴ is alkyl, cycloalkyl or heterocycle that isoptionally substituted by hydroxyl, alkoxy, amine, alkylamine,dialkylamine, —C(O)NH-alkyl, —C(O)N(dialkyl), —NHC(O)-alkyl,—N(alkyl)-C(O)-alkyl.

Customary amidation of commercially available carboxylic acid 12 withIntermediate A affords compound 13, which upon demethylation givescompound 14. Mitsunobu reaction of compound 14 with R²⁴OH, or alkylationof compound 14 with R²⁴Br, R²⁴OMs or R²⁴OTs under basic conditions, suchas K₂CO₃ or Cs₂CO₃ in DMF, THF or CH₃CN, yields compounds of formula of(I-C), where U is CH or N, and R²⁴ is as previously defined herein.

Intermediate B can be made via the process outlined in Scheme 10.

Customary amidation of Intermediate A with carboxylic acid 15 affordsIntermediate B.

Non-commercially available carboxylic acids can be made via the processoutlined in Scheme 11.

Displacement of halogen X (X═F, Cl, Br or I) of compound 16 with cyanousing customary procedures, such as Zn(CN)₂, and catalystPh₂-pentedienone Pd with ligand (Ph₂P)-2-ferrocene in DMF at 100° C. toafford compound 17, which upon hydrolysis under acidic or basicconditions yields Intermediate C.

EXPERIMENTAL SECTION 1. General Methods

Unless specifically stated otherwise, the experimental procedures wereperformed under the following conditions. All operations were carriedout at room temperature (about 18° C. to about 25° C.) under nitrogenatmosphere. Evaporation of solvent was carried out using a rotaryevaporator under reduced pressure or in a high performance solventevaporation system HT-4X (Genevac Inc., Gardiner, N.Y., USA). The courseof the reaction was followed by thin layer chromatography (TLC) orliquid chromatography-mass spectrometry (LC-MS), and reaction times aregiven for illustration only. Silica gel chromatography was carried outon a CombiFlash® system (Teledyne Isco, Inc., Lincoln, Nebr., USA) withpre-packed silica gel cartridge or performed on Merck silica gel 60(230-400 mesh). The structure and purity of all final products wasassured by at least one of the following analytical methods: nuclearmagnetic resonance (NMR) and LC-MS. NMR spectra was recorded on a BrukerAvance™ 300 spectrometer (Bruker BioSpin Corp., Billerica, Mass., USA)or a Varian UNIFY INOVA® 400 (Varian, Inc., Palo Alto, Calif., USA)using the indicated solvent. Chemical shift (δ) is given in parts permillion (ppm) relative to tetramethylsilane (TMS) as an internalstandard. Coupling constants (J) are expressed in hertz (Hz), andconventional abbreviations used for signal shape are: s=singlet;d=doublet; t=triplet; m=multiplet; br=broad; etc. Unless statedotherwise, mass spectra were obtained using electrospray ionization(ESMS) via either a Micromass® Platform 11 system or a Quattro Micro™system (both from Waters Corp., Milford, Mass., USA) and (M+H)⁺isreported.

2. Preparation of Intermediates of the Invention

Unless specified otherwise, the reagents used in the preparation ofcompounds, including intermediates, of the present invention werepurchased from Sigma-Aldrich Corporation (St. Louis, Mo., USA).

Intermediate 1: 6-Methyl-pyridine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide

Intermediate 1 was prepared via the process of Scheme 4, supra, asfollows:

To a flask containing 6-methyl-pyridine-2-carboxylic acid and(3-amino-adamantan-1-yl)-amide (1.0 g, 7 mmol) in DCM (75 mL), was addedDIEA (2 mL, 10 mmol), andbenzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate(3.2 g, 7.3 mmol), followed by a solution of adamantane-1,3-diamine (1.3g, 8 mmol, Zerenex Molecular Ltd., Greater Manchester, UK) in DCM (25mL) dropwise. After stirring at rt for 16 h, the reaction mixture waswashed with saturated sodium bicarbonate. The organic layer was driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified on a reversed phase liquid chromatography/mass spectrometry(RP-HPLC/MS) purification system (Gradient: acetonitrile in water,18-95%, in 3.9 min with a cycle time of 5 min. A shallow gradientbetween 19-30% of acetonitrile was used between 0.7-2.5 min to separateclose-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive:25 mM of ammonium formate. Column: Inertsil® C18, 30×50 mm, 5 μmparticle size (GL Sciences, Tokyo, Japan)) to afford 0.5 g (20%) of thetitle compound, 6-methyl-pyridine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide, as a white solid. NMR (400 MHz, CD₃OD) δ7.89-7.81 (m, 2H), 7.46-7.42 (m, 1H), 2.59 (s, 3H), 2.44-2.06 (m, 6H),2.09-1.67 (m, 8H). ESI-MS m/z: 286.1 (M+H)⁺.

Intermediate 1 was also made via the same synthetic procedures forIntermediate 2 (see below). Starting from3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride (14.9 g,60.8 mmol), coupling with 6-methyl-pyridine-2-carboxylic acid afforded3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acidmethyl ester (14.9 g, 75%). The methyl ester was then hydrolyzed to give3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid(12.2 g, 86%). Finally; the Curtius rearrangement of3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid(10.0 g, 31.8 mmol) yielded Intermediate 1 (8.48 g, 93%).

Intermediate 2: Pyridine-2-Carboxylic acid(3-amino-adamantan-1-yl)-amide

Intermediate 2 was synthesized via the process of Scheme 5, supra, asfollows:

Step 1: 3-Acetylamino-adamantane-1-carboxylic acid

To a 10-L reactor was added 1-adamantanecarboxylic acid (503 g, 2.79mol; TCI America, Wellesley Hills, Mass., USA) and 70% nitric acid (400mL, 6.72 mol), and the resulting suspension was cooled at 0° C. with arecirculating chiller. To the mixture was slowly added 98% sulfuric acid(3.00 L, 55.5 mol) at such a rate that the temperature was kept below10° C. Once the addition completed, acetonitrile (2.00 L, 38.5 mol) wasadded at such a rate that the temperature was kept below 10° C. Afterall the acetonitrile was added, the reaction was stirred at 0° C. for 1hour. The crude reaction was then added to a 20-L reactor filled withabout 10-L of ice mixed with a small amount of water and the resultingmixture was stirred and allowed to warm to room temperature. The solidswere then filtered and washed with water. More solids precipitated fromthe acidic aqueous layer and these were filtered as well and washed withwater. The combined solid material was then dried under high vacuum at50° C. for 2 days to afford 432 g (73%) of the title compound,3-acetylamino-adamantane-1-carboxylic acid, as a white solid.

Step 2: 3-Amino-adamantane-1-carboxylic acid hydrochloride

To a 3-neck 5 L, flask equipped with a reflux condenser, a mechanicalstirrer and a temperature probe was added3-acetylamino-adamantane-1-carboxylic acid (432 g, 1.82 mol), water(1.00 L) and concentrated hydrochloric acid (2.44 L), and the resultingmixture was heated at 95° C. for 6 days. During this time, solidmaterial precipitated from the solution. After cooling at 0° C., thesolids were filtered and washed with acetone. The solid was then driedunder high vacuum at 50° C. for about 2 hours to afford 328 g (78%) ofthe title compound, 3-amino-adamantane-1-carboxylic acid hydrochloride,as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.35 (br s, 1H), 8.27 (brs, 3H), 2.22-2.12 (m, 2H), 1.92-1.85 (m, 2H), 1.83-1.71 (m, 6H),1.69-1.48 (m, 4H).

Step 3: 3-Amino-adamantane-1-carboxylic acid methyl ester hydrochloride

To a 3-neck 2-L flask equipped with a reflux condenser and a temperatureprobe was added 3-amino-adamantane-1-carboxylic acid hydrochloride (100g, 432 mmol) and methanol (1.0 L). To this solution was slowly addedthionyl chloride (15.7 mL, 216 mmol) and the reaction was heated at 60°C. for 4 hours. Once cooled to room temperature, the crude reactionmixture was concentrated under reduced pressure to remove most of themethanol. Heptane (about 1-L) was then added and the mixture was onceagain concentrated under reduced pressure at which point a solid beganto precipitate. This process was repeated three more times, then thesolids were filtered off, washed with heptane and allowed to dry in openair to afford 97.2 g (92%) of the title compound,3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride, as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 8.46 (br s, 3H), 3.65 (s, 3H),2.33-2.24 (m, 2H), 2.23-2.16 (m, 2H), 2.11-1.95 (m, 4H), 1.94-1.78 (m,4H), 1.75-1.62 (m, 2H).

Step 4: 3-[(Pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acidmethyl ester

To a round bottom flask was added 3-amino-adamantine-1-carboxylic acidmethyl ester hydrochloride (20.0 g, 81.4 mmol) and methylene chloride(500 mL) and the solution was cooled at 0° C. To this solution was thenadded triethylamine (57 mL, 0.41 mol) followed by picolinoyl chloridehydrochloride (15.2 g, 85.4 mmol; TCI America, Wellesley Hills, Mass.,USA) and the reaction was stirred at 0° C. for 30 minutes, then at roomtemperature for 6 hours. To the reaction was added saturated aqueoussodium bicarbonate (500 mL) and the biphasic mixture was stirredvigorously for a few minutes, then transferred to a 2-L separatoryfunnel. The mixture was extracted, the layers separated and the aqueouslayer was extracted again with methylene chloride (2×200 mL). Thecombined organic layers were washed with brine (300 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure toafford 24.8 g (97%) of the title compound,3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methylester, as a pale brown solid. ¹H NMR (400 MHz, CDCl₃) δ 8.54-8.49 (m,1H), 8.16 (dt, J=7.8, 1.0 Hz, 1H), 7.96 (br s, 1H), 7.83 (td, J=7.8, 1.8Hz, 1H), 7.40 (ddd, J=7.6, 4.8, 1.3 Hz, 1H), 3.66 (s, 3H), 2.34-2.30 (m,2H), 2.29-2.23 (m, 2H), 2.17-2.13 (m, 4H), 1.97-1.80 (m, 4H), 1.78-1.62(m, 2H). ESI-MS m/z: 315.0 (M+H)⁺.

Step 5: 3-[(Pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid

To a round bottom flask was added3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methylester (24.8 g, 78.9 mmol), tetrahydrofuran (250 mL), water (250 mL) andlithium hydroxide monohydrate (14.9 g, 355 mmol) and the mixture wasstirred vigorously at room temperature for 25 hours. The crude mixturewas concentrated under reduced pressure to remove most of thetetrahydrofuran, then the aqueous solution was diluted with water (200mL) and the pH was adjusted to about 3-4 by adding solid citric acidmonohydrate. A voluminous white precipitate appeared which was filtered,washed with water and dried under high vacuum at 50° C. to afford 22.1 g(93%) of the title compound,3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid, as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 8.55-8.50 (m, 1H), 8.18 (d, J=7.7 Hz,1H), 7.97 (br s, 1H), 7.85 (td, J=7.8, 1.8 Hz, 1H), 7.42 (ddd, J=7.6,4.8, 1.3 Hz, 1H), 2.35-2.31 (m, 2H), 2.31-2.25 (m, 2H), 2.25-2.09 (m,4H), 2.00-1.86 (m, 4H), 1.80-1.64 (m, 2H). ESI-MS m/z: 301.0 (M+H)⁺.

Step 6: Pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide

To a round bottom flask was added3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid (10.0 g,33.3 mmol) and toluene (100 mL). To the suspension was addedtriethylamine (5.6 mL, 40 mmol) and the mixture was stirred for a fewminutes until most of the solids were dissolved. To the mixture was thenadded diphenylphosphonic azide (7.9 mL, 37 mmol) and the reaction wasstirred at room temperature for 1 hour. The reaction mixture wastransferred to an addition funnel and added dropwise to a 3-neck roundbottom flask equipped with a reflux condenser containing toluene (70 mL)heated at 90° C. After the addition, the reaction was stirred at 90° C.for two more hours, then allowed to cool down to room temperature. Thereaction mixture was then slowly added to a flask containing 6.0 Naqueous hydrochloric acid (55 mL, 330 mmol) and stirred vigorously for 1hour. The biphasic mixture was transferred to a separatory funnel andthe toluene layer was discarded. The aqueous acidic layer was thenslowly treated with solid sodium carbonate until a pH of 10 wasobtained. The aqueous layer was transferred to a 500-mL separatoryfunnel and extracted with methylene chloride (3×100 mL). The combinedorganic layers were then washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure to afford 8.38 g (93%)of the title compound, pyridine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide, as a gummy foam. ¹H NMR (300 MHz, CDCl₃)δ 8.55-8.50 (m, 1H), 8.16 (d, J=7.9 Hz, 1H), 7.94 (br s, 1H). 7.84 (td,J=7.7, 1.7 Hz, 1H), 7.40 (ddd, J=7.6, 4.7, 1.3 Hz, 1H), 2.31-2.21 (m,2H), 2.13-1.97 (m, 6H), 1.71-1.51 (m, 6H). ESI-MS m/z: 272 (M+H)⁺.

Intermediate 2 was also made via the process of Scheme 6, supra, asfollows:

Step 1: Pyridine-2-carboxylic acid (3-hydroxy-adamantan-1-yl)-amide

To a 40 ml vial was added picolinic acid (0.68 g, 5.5 mmol), DMF (15ml), triethylamine (0.90 mL, 6.4 mmol), andO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 2.3 g, 6.0 mmol). The mixture was stirred at rt for 5 minutes toget a clear solution. 3-Amino-adamantanol (0.84 g, 5.0 mmol; AKScientific, 897-4G Independence Ave., Mountain View, Calif. 94043) wasadded to the above solution and stirred at rt for 2 hours. DMF wasremoved in Genevac and the residue was dissolved in DCM (20 mL), washedwith 1N aqueous NaOH, water and brine, dried over Na₂SO₄, andconcentrated under reduced pressure to afford 1.32 g (97%) of crudetitle compound, pyridine-2-carboxylic acid(3-hydroxy-adamantan-1-yl)-amide, as an oil, which became a colorlesssolid upon standing at room temperature. LC/MS (Gradient: acetonitrilein water, 20-85%, in 1.7 minutes with a cycle time of 2 min. Flow rate:5.0 mL/min. Mobile phase additive: 30 mM of ammonium formate. Column:Inertse ODS-3, 50×4.6 mm, 3 μm particle size (GL Sciences, Tokyo,Japan)): Retention time: 0.79 min; purity (UV₂₅₄): 100%; ESI-MS m/z: 273(M+H)⁺. It was used in the next step without further purification.

Step 2: Pyridine-2-carboxylic acid[3-(2-chloro-acetylamino)-adamantan-1-yl]-amide

Chloroacetonitrile (2.0 mL, 32 mmol) was cooled to 0° C. Sulfuric acid(1.0 mL, 19 mmol) was added slowly at 0° C. After addition completed,the mixture was stirred at 0° C. for 5 minutes. Pyridine-2-carboxylicacid (3-hydroxy-adamantan-1-yl)-amide (0.42 g, 1.56 mmol, from step 1)was added in one portion and the mixture was stirred at rt overnight.The thick solution was poured into ice-water (10 mL). DCM (10 mL) wasadded. While the mixture was cooled with an ice-bath, the pH of theaqueous phase (top) was adjusted to 10-13 with 10 N aq. NaOH. Theaqueous layer was extracted with DCM. The combined organic layer waswashed with water and brine, dried over Na₂SO₄, and concentrated underreduced pressure to afford 0.53 g (96.9%) of crude title compound,pyridine-2-carboxylic acid[3-(2-chloro-acetylamino)-adamantan-1-yl]-amide, as an oil, which becamea colorless solid upon standing at room temperature. LC-MS (Gradient:acetonitrile in water, 20-85%, in 1.7 minutes with a cycle time of 2min. Flow rate: 5.0 mL/min. Mobile phase additive: 30 mM of ammoniumformate. Column: Inertsil® ODS, 50×4.6 mm, 3 μm particle size (GLSciences, Tokyo, Japan)): Retention time: 1.08 min; purity (UV₂₅₄):100%; ESI-MS m/z: 348 (M+H)⁺. It was used in the next step withoutfurther purification.

Step 3: Pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide

To a 40 ml vial containing pyridine-2-carboxylic acid[3-(2-chloro-acetylamino) adamantan-1-yl]-amide (1.69 g, 4.85 mmol, fromstep 2) and thiourea (0.56 g, 7.4 mmol), was added ethanol (20.0 mL),and acetic acid (4.0 mL). The mixture was stirred at 78° C. overnight.The reaction solution was cooled to rt, poured into water (100 mL), andthe pH of the solution was adjusted to 10-13 using 10 N aq. NaOH. Themixture vas transferred into a separation funnel, extracted with DCM(3×150 mL). Combined organic layer was washed with water and brine,dried over Na₂SO₄, and concentrated under reduced pressure to afford1.35 g (95.4%) of crude title compound, pyridine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide, as an oil, which became a colorlesssolid upon standing at room temperature. LC-MS (Gradient: acetonitrilein water, 10-85%, in 1.7 minutes with a cycle time of 2 min. Flow rate:5.0 mL/min. Mobile phase additive: 30 mM of ammonium formate. Column:Inertsil® C8, 50×4.6 mm, 3 μm particle size (GL Sciences, Tokyo,Japan)): Retention time: 0.63 min; purity (UV₂₅₄): 93%; ESI-MS m/z: 272(M+H)⁺. It was used in the next step, amidation, without furtherpurification.

Intermediate 3: N-(3-Amino-adamantan-1-yl)-3-fluoro-benzamide

Using the same procedures as in the synthesis of Intermediate 2,Intermediate 3 was made at 4.33 mmol reaction scale, and 1.26 g (95.6%)of crude product was obtained. LC-MS (Gradient: acetonitrile in water,10-85%, in 1.7 minutes with a cycle time of 2 min. Flow rate: 5.0mL/min. Mobile phase additive: 30 mM of ammonium formate. Column:Inertsil® C8, 50×4.6 mm, 3 μm particle size (GL Sciences, Tokyo,Japan)): Retention time: 0.70 min; purity (UV₂₅₄): 95%. ESI-MS m/z: 289(M+H)⁺. It was used in the next step without further purification.

Intermediate 4: 6-Chloro-pyridine-2-carboxylic acid{3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide

Intermediate 4 was prepared from Intermediate 2 via the process ofScheme 10, supra, as follows:

To a 40 ml vial was added 6-chloropyridine-2-carboxylic acid (0.79 g,5.0 mmol), DMF (15 ml), triethylamine (0.90 mL, 6.4 mmol), andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(2.3 g, 6.0 mmol). The mixture was stirred at room temperature for 5minutes to get a clear solution. Pyridine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide (Intermediate 2, 1.38 g, 4.73 mmol) wasadded to the solution, and the reaction mixture was stirred at roomtemperature for 2 hours. DMF was removed in Genevac. The residue wasdissolved in DCM (20 mL), washed with aq. 1 N NaOH (15 mL), water (15mL) and brine (15 mL), and dried over Na₂SO₄. Solvent was removed underreduced pressure to afford 1.85 g (95.2%) of crude title compound,6-chloro-pyridine-2-carboxylic acid{3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide. LC-MS (Gradient:acetonitrile in water, 30-90%, in 1.7 minutes with a cycle time of 2min. Flow rate: 5.0 mL/min. Mobile phase additive: 30 mM of ammoniumformate. Column: Inertse C8, 50×4.6 mm, 3 μm particle size (GL Sciences,Tokyo, Japan)): Retention time: 1.17 min; purity (UV₂₅₄): 100%. ESI-MSm/z: 411 (M+H)⁺. It was used in the next step without furtherpurification.

Intermediate 5: 6-Chloro-pyridine-2-carboxylic acid{3-[(6-methylpyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide

In a similar manner to Intermediate 4, Intermediate 5 was prepared fromIntermediate 1 (2.00 g, 7.01 mmol). After purification by silica gelchromatography, Intermediate 5 (1.94 g, 65%) was obtained as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 8.13 (br s, 1H), 8.09 (d, J=7.5 Hz,1H), 7.98 (d, J=7.7 Hz, 1H), 7.84-7.69 (m, 3H), 7.44 (d, J=7.7 Hz, 1H),7.26 (d, 1H), 2.60-2.55 (m, 5H), 2.40-2.32 (m, 2H), 2.31-2.12 (m, 8H),1.76-1.70 (m, 2H). ESI-MS m/z: 425.0 (M+H)⁺.

Intermediate 6: 6-Chloro-pyridine-2-carboxylic acid[3-(3-fluoro-benzoylamino)-adamantan-1-yl]-amide

In a similar manner to Intermediate 4, Intermediate 6 was prepared fromIntermediate 3 at a 4.6 mmol reaction scale. Crude product (1.99 g, 97%)was obtained. LC-MS (Gradient: acetonitrile in water, 30-90%, in 1.7minutes with a cycle time of 2 min. Flow rate: 5.0 mL/min. Mobile phaseadditive: 30 mM of ammonium formate. Column: Inertse C8, 50×4.6 mm, 3μmparticle size (GL Sciences, Tokyo, Japan)): Retention time: 1.21 min;purity (UV₂₅₄):100%. ESI-MS m/z: 428 (M+H)⁺. It was used in the nextstep without further purification.

Intermediate 7: Pyrazine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide

Intermediate 7 was synthesized via the process of Scheme 5 from compound4, supra, as follows:

Step 1: 3-[(Pyrazine-2-carbonyl)-amino]-adamantane-1-carboxylic acid

To a round bottom flask was added 3-amino-adamantane-1-carboxylic acidmethyl ester hydrochloride (7.00 g, 28.5 mmol), 2-pyrazinecarboxylicacid (3.71 g, 29.9 mmol) and methylene chloride (200 mL). The mixturewas stirred vigorously and treated with PyBOP® (15.6 g, 29.9 mmol)followed by triethylamine (9.9 mL, 71 mmol), and then stirred at roomtemperature for 16 hours. To the reaction was added saturated aqueoussodium bicarbonate (200 mL) and the biphasic mixture was stirredvigorously for a few minutes, then transferred to a 1-L separatoryfunnel. The mixture was extracted, the layers separated and the aqueouslayer was extracted again with methylene chloride (200 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue was thendissolved in tetrahydrofuran (200 mL) and water (200 mL) was added. Tothe biphasic mixture was added lithium hydroxide monohydrate (5.38 g,128 mmol), and the resultant mixture stirred vigorously at roomtemperature for 22 hours. Most of the volatiles were removed underreduced pressure and the resulting aqueous solution was transferred to a500-mL separatory funnel and washed with methylene chloride (3×150 mL).The aqueous layer was diluted with water (200 mL) and the pH wasadjusted to about 3-4 by adding solid citric acid monohydrate. Avoluminous white precipitate appeared that was filtered, washed withwater and dried under high vacuum at 50° C. to afford 8.11 g (95%) ofthe title compound,3-[(pyrazine-2-carbonyl)-amino]-adamantane-1-carboxylic acid, as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 11.14-10.07 (br s, 1H), 9.38 (d, J=1.5Hz, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.50 (dd, J=2.4, 1.5 Hz, 1H), 7.68 (brs, 1H), 2.35-2.25 (m, 4H), 2.23-2.08 (m, 4H), 2.00-1.86 (m, 4H),1.81-1.64 (m, 2H). ESI-MS m/z: 301.9 (M+H)⁺.

Step 2: Pyrazine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide

Using the same procedure as that used to prepare Intermediate 2 in step6, from 3-[(pyrazine-2-carbonyl)-amino]-adamantane-1-carboxylic acid(4.00 g, 13.3 mmol), the Curtius rearrangement afforded 3.56 g (99%) ofthe title compound, pyrazine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide, as an off-white solid. ¹H NMR (300 MHz,CDCl₃) δ 9.37 (d, J=1.4 Hz, 1H), 8.73 (d, J=2.5 Hz, 1H), 8.49 (dd,J=2.4, 1.5 Hz, 1H), 7.64 (br s, 1H), 2.31-2.21 (m, 2H), 2.14-1.95 (m,6H), 1.71-1.51 (m, 6H) (Note: the —NH₂ is hidden between 2.52-1.78 ppm).ESI-MS m/z: 273.0 (M+H)⁺.

Intermediate 8: 6-Methyl-pyrazine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide

Intermediate 8 was synthesized via the process of Scheme 5 from compound4, supra, as follows:

Step 1: 3-[(6-Methyl-pyrazine-2-carbonyl)-amino]-adamantane-1-carboxylicacid

Using the same procedure as that used to prepare Intermediate 7 in step1, from 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride(7.00 g, 28.5 mmol) and 6-methylpyrazine-2-carboxylic acid (4.13 g, 29.9mmol, RihaChem, Kostalov Czech Republic), the coupling reaction withPyBOP®, followed by basic hydrolysis of the methyl ester group, afforded8.01 g (89%) of the title compound,3-[(6-methyl-pyrazine-2-carbonyl)-amino]-adamantane-1-carboxylic acid,as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 12.03-10.32 (br s, 1H), 9.17(s, 1H), 8.60 (s, 1H), 7.72 (br s, 1H), 2.60 (s, 3H), 2.35-2.26 (m, 4H),2.26-2.18 (m, 2H), 2.16-2.07 (m, 2H), 2.00-1.86 (m, 4H), 1.80-1.65 (m,2H). ESI-MS m/z: 316.0 (M+H)⁺.

Step 2: 6-Methyl-pyrazine-2-carboxylic acid (3-amino-adamantan-1-yl)amide

Using the same procedure as that used to prepare Intermediate 2 in step6, from 3-[(6-methyl-pyrazine-2-carbonyl)-amino]-adamantane-1-carboxylicacid (3.00 g, 9.51 mmol), the Curtius rearrangement afforded 2.65 g(97%) of the title compound, 6-methyl-pyrazine-2-carboxylic acid(3-amino-adamantan-1-yl) amide, as an off-white solid. ¹H NMR (400 MHz,CDCl₃) δ 9.17 (s, 1H), 8.59 (s, 1H), 7.69 (br s, 1H), 2.60 (s, 3H),2.32-2.21 (m, 2H), 2.13-1.97 (m, 6H), 1.70-1.52 (m, 6H) (Note: the —NH₂is hidden between 2.41-1.29 ppm). ESI-MS m/z: 287.0 (M+H)⁺.

Intermediate 9: Pyrimidine-4-carboxylic acid(3-amino-adamantan-1-yl)-amide

Using the same procedures as in the synthesis of Intermediate 7,Intermediate 9 was made at 16.8 mmol reaction scale from3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride andpyrimidine-4-carboxylic acid (Ark Pharm Inc., Libertyville, Ill., USA),and 4.00 g (88%) of crude product was obtained. LC-MS (Gradient:acetonitrile in water, 20-85%, in 1.7 minutes with a cycle time of 2min. Flow rate: 5.0 mL/min. Mobile phase additive: 30 mM of ammoniumformate. Column: Inertsil® ODS, 50×4.6 mm, 3 μm particle size (GLSciences)): Retention time: 0.24 min; purity (UV₂₅₄): 95%. ESI-MS m/z:273 (M+H)⁺. It was used in the next step without further purification.

Intermediate 10: 2-Methyl-pyrimidine-4-carboxylic acid(3-amino-adamantan-1-yl)-amide

Using the same procedures as in the synthesis of Intermediate 7,Intermediate 10 was made at 15.8 mmol reaction scale from3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride and2-methyl-pyrimidine-4-carboxylic acid (Ark Pharm Inc.), and 4.6 g (100%)of crude product was obtained. LC-MS (Gradient: acetonitrile in water,20-85%, in 1.7 minutes with a cycle time of 2 min. Flow rate: 5.0mL/min. Mobile phase additive: 30 mM of ammonium formate. Column:Inertsil® ODS, 50×4.6 mm, 3 μm particle size (GL Sciences)): Retentiontime: 0.30 min; purity (UV₂₅₄): 82%. ESI-MS m/z: 287 (M+H)⁺. It was usedin the next step without further purification.

Intermediate 11: 4-Trifluoromethyl-pyrimidine-2-carboxylic acid

Intermediate 11 was made via the process of Scheme 11, supra, asfollows:

Step 1: 4-Trifluoromethyl-pyrimidine-2-carbonitrile

To a solution 2-chloro-4-(trifluoromethyl)pyrimidine (5.00 g, 27.4 mmol)in dimethyl sulfoxide (25 mL) was added sodium cyanide (1.68 g, 34.2mmol). The reaction was stirred at room temperature for 30 minutes andpoured into cold saturated aqueous NaHCO₃ solution. The mixture wastransferred to a 100 mL separatory funnel and extracted with ethyl ether(3×50 mL). The combined organic layers were washed with brine (50 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure to afford the title compound,4-trifluoromethyl-pyrimidine-2-carbonitrile, as a brown oil, which wasused in the next step without further purification. ¹H NMR (400 MHz,CDCl₃) δ9.16 (d, J=5.1 Hz, 1H), 7.88 (d, J=5.1 Hz, 1H).

Step 2: 4-Trifluoromethyl-pyrimidine-2-carboxylic acid

The crude 4-trifluoromethyl-pyrimidine-2-carbonitrile from Step 1 wasdissolved in a solution of hydrogen chloride in water (6 M, 20.0 mL) andheated at reflux temperature overnight. The reaction mixture was cooledto room temperature, and concentrated under reduced pressure. Toluene(20 mL) was then added and the mixture was concentrated under reducedpressure. This process was repeated with 1,4-dioxane and ethyl ether,then the solids were filtered off. The filtrate was concentrated underreduced pressure to afford 4.80 g (82.1%) of the title compound,4-tritluoromethyl-pyridine-2-carboxylic acid, as brown solid, which wasused in the next step without further purification. ¹H NMR (400 MHz,DMSO-d6) δ9.35 (d, J=5.0 Hz, 1H), 8.25 (d, J=5.1 Hz, 1H).

Intermediate 12: 4-Methyl-pyrimidine-2-carboxylic acid

Step 1: 4-Methyl-pyrimidine-2-carbonitrile

To a solution of 2-chloro-4-methylpyrimidine (3.00 g, 23.3 mmol; 3BPharmachem International, China) in ethyl ether (24 mL) was added asolution of sodium cyanide (2.86 g, 58.3 mmol) in trimethylaminesolution (1:3, trimethylamine:water, 24.0 mL). The reaction mixture wasstirred at room temperature overnight. The aqueous layer was extractedwith ethyl ether (3×20 mL). The combined organic layers were dried overMgSO₄, filtered, and concentrated under reduced pressure to yield thetitle compound, 4-methyl-pyrimidine-2-carbonitrile (1.80 g; 64.8%),which was used in the next step without further purification. ¹H NMR(400 MHz, D₂O) δ8.64 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.5 Hz, 1H).

Step 2: 4-Methyl-pyrimidine-2-carboxylic acid

The solution of 4-methyl-pyrimidine-2-carbonitrile (500 mg, 4.20 mmol)and sodium hydroxide (504 mg, 12.6 mmol) in water (12.5 mL) was stirredat 60° C. for 1 hour. The reaction mixture was cooled to roomtemperature, acidified to pH ˜2 with citric acid and extracted withCHCl₃:i-PrOH (3:1, 2×20 mL). The combined organic layers were dried overMgSO₄ and concentrated under reduced pressure to afford 0.294 g of thetitle compound, 4-methyl-2-pyrimidinecarboxylic acid (51%), which wasused in the next step without further purification. ¹H NMR (300 MHz,D₂O) δ8.50 (d, J=5.2 Hz, 1H), 7.31 (d, J=5.3 Hz, 1H).

3. Preparation of Compounds of the Invention

Unless specified otherwise, the reagents used in the preparation ofcompounds, including intermediates, of the present invention werepurchased from Sigma-Aldrich Corporation (St. Louis, Mo., USA).

Example 1 N,N′-(1,3-adamantylene)bis(6-methyl-pyridine-2-carboxamide)

Example 1 was prepared via the process of Scheme 1, supra, as follows:

To a vial containing 6-methyl picolinic acid (40 mg, 0.3 mmol),methylene chloride (10 mL) and N,N-diisopropylethylamine (60 mg, 0.5mmol), was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (60 mg, 0.3 mmol). The mixture was stirred for 5 minutes.Adamantane-1,3-diamine hydrochloride salt (20 mg, 0.1 mmol; Zerenex™Molecular Ltd., Greater Manchester, UK) was added and the reaction wasallowed to proceed for 16 h. The reaction mixture was washed withsaturated sodium bicarbonate, dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified on a reversed phaseliquid chromatography/mass spectrometry (RP-HPLC/MS) purification system(Gradient: acetonitrile in water, 25-95%, in 3.9 min with a cycle timeof 5 min. A shallow gradient between 28-58% of acetonitrile was usedbetween 0.75-3.5 min to separate close-eluting impurities. Flow rate:100 mL/min. Mobile phase additive: 25 mM of ammonium acetate. Column:Inertsil® C8, 30×50 mm, 5 um particle size) to afford the title compound(33 mg, 80%) as an off white oil. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, br,2H), 7.96 (d, J=7.76 Hz, 2H), 7.70 (t, J=7.70 Hz, 2H), 7.27-7.22 (m,2H), 2.58-2.55 (m, 2H), 2.38-2.13 (m, 10H). 1.75-1.71 (m, 2H). ESI-MSm/z: 405.0 (M+H)⁺.

Example 2 N,N′-(1,3-adamantylene)bis(2-pyridinecarboxamide)

Example 2 was prepared via the process of Scheme 1, supra, as follows:

Into a vial containing adamantane-1,3-diamine (50 mg, 0.3 mmol; Zerenex™Molecular Ltd., Greater Manchester, UK) and methylene chloride (10 mL)at 0° C. was added N,N-diisopropylethylamine (200 mg, 2 mmol; AlfaAesar®, Ward Hill, Mass., USA). Into the reaction was addedpyridine-2-carbonyl chloride (60 mg, 0.4 mmol; TCI America, WellesleyHills, Mass., USA). After stirring at room temperature for 16 h, thereaction mixture was washed with saturated sodium bicarbonate, driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified on a reversed phase liquid chromatography/mass spectrometry(RP-HPLC/MS) purification system (Gradient: acetonitrile in water,30-95%, in 3.9 min with a cycle time of 5 min. Flow rate: 100 mL/min.Mobile phase additive: 25 mM of ammonium formate. Column: Inertsil® C8,30×50 mm, 5 um particle size) to obtain the title compound as a brownishoil. (58 mg, 50%). ¹H NMR (300 MHz, CDCl₃) δ 8.51 (d, J=4.86 Hz, 2H),8.15 (d, J=7.85 Hz, 2H), 8.03 (s, br 2H), 7.83 (d, J=7.70 Hz, 2H),7.43-7.37 (m, 2H), 2.58 (s, br, 2H), 2.38-2.31 (m, 2H). 2.20-2.13 (m,8H), 1.76-1.71 (m, 2H). ESI-MS m/z: 377.0 (M+H)⁺.

In an analogous manner to Example 2, Examples 3-5 of Table 1 (below)were made from commercially available aryl or heteroaryl carbonylchloride on 0.1 to 0.3 mmol reaction scales.

Example 6 Pyridine-2-carboxylic acid[3-(3-chloro-benzoylamino)-adamantan-1-yl]-amide

Example 6 was prepared via the process of Schemes 4 and 3, supra, asfollows:

To a vial containing adamantane-1,3-diamine (50 mg, 0.3 mmol) andtetrahydrofuran (5 mL) was added dropwise, 5M aq NaOH (0.6 mL, 3 mmol).With vigorous stirring, picolinoyl chloride hydrochloride (50 mg, 0.3mmol) was added in portions. After stirring at room temperature for 16h, the reaction mixture was partitioned into dichloromethane andsaturated sodium bicarbonate. The organic layer was dried over sodiumsulfate and concentrated under reduced pressure. The residue was retakeninto 5 mL of DCM (dichloromethane). To the suspension was added DIEA(N,N-diisopropyl-ethylamine) (160 mg, 1.2 mmol) and 3-chloro-benzoylchloride (79 mg, 0.45 mmol). The reaction mixture was stirred at roomtemperature for 16 h, washed with saturated sodium bicarbonate, driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified on a reversed phase liquid chromatography/mass spectrometry(RP-HPLC/MS) purification system (Gradient: acetonitrile in water,25-95%, in 3.9 min with a cycle time of 5 min. A shallow gradientbetween 35-65% of acetonitrile was used between 0.75-3.5 min to separateclose-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive:25 mM of ammonium acetate. Column: Inertsil® C8, 30×50 mm, 5 um particlesize) to afford the title compound (28 mg, 22%) as an off white oil. ¹HNMR (400 MHz, CDCl₃) δ 8.51 (d, J=4.75 Hz, 1H), 8.15 (d, J=7.84 Hz, 1H),8.03 (s, br 1H), 7.83 (t, J=7.72 Hz, 1H), 7.69 (t, J=1.82 Hz, 1H), 7.57(d, J=7.60 Hz, 1H), 7.46-7.31 (m, 3H), 5.87 (s, br 1H), 2.56 (s, br,2H), 2.38-2.31 (m, 2H). 2.24-2.12 (m, 8H), 1.76-1.69 (m, 2H). ESI-MSm/z: 410.0 (M+H)⁴.

In an analogous manner to Example 6, Examples 7-10 in Table 1 (below)were made from commercially available aryl or heteroaryl carbonylchloride on a 0.3 mmol reaction scale.

Example 11 N,N′-(1,3-Adamantylene)bis(4-methyl-pyridine-2-carboxamide)

Example 11 was synthesized via the process of Scheme 1, supra, asfollows:

To a vial containing 4-methyl-pyridine-2-carboxylic acid (30 mg, 0.22mmol) in DMF (1 mL), was addedbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (97 mg, 0.22 mmol), DIEA (40 mg, 0.3 mmol; AlfaAesar, Ward Hill, Mass., USA), followed by adamantane-1,3-diamine (20mg, 0.1 mmol in 1 mL of THF; Zerenex Molecular Ltd., Greater Manchester,UK). After stirring for 16 h at rt, the reaction mixture was partitionedinto dichloromethane and saturated sodium bicarbonate. The organic layerwas dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified on a reversed phase liquidchromatography/mass spectrometry (RP-HPLC/MS) purification system(Gradient: acetonitrile in water, 30-95%, in 3.7 minutes with a cycletime of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 25 mM ofammonium formate. Column: Inertsil® C8, 30×5.0 mm, 5 μm particle size(GL Sciences, Tokyo, Japan)) to afford 18 mg (40%) of the titlecompound, N,N′-(1,3-adamantylene)bis(4-methyl-pyridine-2-carboxamide, asan off-white oil. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J=4.9 Hz, 2H), 8.02(s, br, 2H), 7.98-7.96 (m, 2H), 7.21-7.19 (m, 2H), 2.57-2.55 (m, 2H),2.41 (s, 6H), 2.36-2.31 (m, 2H), 2.25-2.13 (m, 8H), 1.74-1.70 (m, 2H).ESI-MS m/z: 405.0 (M+H)⁺.

In an analogous manner to Example 11, Examples 12-16 in Table 1 (below)were made from commercially available aryl or heteroaryl carboxylicacids on 0.1 to 0.3 mmol reaction scales.

Example 17N,N′-(1,3-Adamantylene)bis(1-methyl-1H-pyrazole-3-carboxamide)

Example 17 was synthesized from heteroaryl carbonyl chloride via theprocess of Scheme 1, supra, as follows:

To a solution of adamantane-1,3-diamine (20 mg, 0.1 mmol; ZerenexMolecular Ltd., Greater Manchester, UK) in THF (4 mL), was added1-methyl-1H-pyrazole-3-carbonyl chloride (40 mg, 0.3 mmol) and DIEA (40mg, 0.3 mmol). After stirring for 16 h at rt, the reaction mixture waspartitioned into dichloromethane and saturated sodium bicarbonate. Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified on a RP-HPLC/MSpurification system (Gradient: acetonitrile in water, 18-95%, in 3.9minutes with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phaseadditive: 25 mM of ammonium acetate. Column: Inertsil® C8, 30×50 mm, 5μm particle size (GL Sciences, Tokyo, Japan)) to afford 19 mg (50%) ofthe title compound,N,N′-(1,3-adamantylene)bis(1-methyl-1H-pyrazole-3-carboxamide, as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.32 (d, J=2.3 Hz, 2H),6.74-6.71 (m, 4H), 3.89 (s, 6H), 2.49 (s, br, 2H), 2.33-2.26 (m, 2H),2.23-2.06 (m, 8H), 1.72-1.64 (m, 2H). ESI-MS m/z: 383.1 (M+H)⁺.

Example 18 5-Methyl-pyrazine-2-carboxylic acid{3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide

Example 18 was synthesized via the process of Scheme 2 usingcommercially available carboxylic acids, supra, as follows:

To a solution of adamantane-1,3-diamine (20 mg, 0.1 mmol; ZerenexMolecular Ltd., Greater Manchester, UK) in DCM (2 mL) was added DIEA (26mg, 0.15 mmol), 1-methyl-1H-pyrazole-3-carboxylic acid (14 mg, 0.11mmol), 5-methyl-pyrazine-2-carboxylic acid (15 mg, 0.11 mmol) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (110mg, 0.20 mmol). After stirring for 3 hours at rt, the reaction mixturewas partitioned into dichloromethane and saturated sodium bicarbonate.The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified on aRP-HPLC/MS purification system (Gradient: acetonitrile in water, 25-95%,in 14 minutes with a cycle time of 5 min. A shallow gradient between25-50% of acetonitrile was used between 0.75-3.3 min to separateclose-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive:25 mM of ammonium formate. Column: Inertsil® C8, 30×50 mm, 5 μm particlesize (GL Sciences, Tokyo, Japan)) to afford 15 mg (37%) of the titlecompound, 5-methyl-pyrazine-2-carboxylic acid{3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide, as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ9.22 (s, 1H), 8.34-8.33 (m, 1H),7.67 (s, br, 1H), 7.33 (d, J=2.3 Hz, 1H), 6.76-6.72 (m, 2H), 3.89 (s,3H), 2.64 (s, 3H), 2.54 (s, br, 2H), 2.37-2.09 (m, 10H), 1.73-1.68 (m,2H). ESI-MS m/z: 395.0 (M+H)⁺.

Example 19 Thiazole-2-carboxylic acid{3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide

Example 19 was synthesized via the process of Scheme 2 usingcommercially available carboxylic acid chlorides, supra, as follows:

To a solution of adamantane-1,3-diamine (17 mg, 0.1 mmol, ZerenexMolecular Ltd., Greater Manchester, UK) in DCM (2 mL) was added DIEA (20mg, 0.15 mmol), 1-methyl-1H-pyrazole-3-carbonyl chloride (16 mg, 0.11mmol; Maybridge Chemical Co., Cornwall, UK) and thiazole-2-carbonylchloride (16 mg, 0.11 mmol; Maybridge Chemical Co., Cornwall, UK). Afterstirring at room temperature for 3 h, the reaction mixture waspartitioned into dichloromethane and saturated sodium bicarbonate. Theorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The residue was purified on a RP-HPLC/MS purificationsystem (Gradient: acetonitrile in water, 25-95%, in 3.9 minutes with acycle time of 5 min. A shallow gradient between 27-53% of acetonitrilewas used between 0.75-3.3 min to separate close-eluting impurities. Flowrate: 100 mL/min. Mobile phase additive: 25 mM of ammonium formate.Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo,Japan)) to afford 15 mg (38%) of the title compound,thiazole-2-carboxylic acid{3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide, as acolorless oil. ¹H NMR (400 MHz, CDCl₃) (57.81 (d, J=3.2 Hz, 1H), 7.53(d, J=3.2 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H),6.74-6.71 (m, 2H), 3.89 (s, 3H), 2.55-2.51 (m, 2H), 2.35-2.29 (m, 2H),2.19-2.11 (m, 8H), 1.71-1.67 (m, 2H), ESI-MS m/z: 386.0 (M+H)⁺.

Example 20 6-Methyl-pyridine-2-carboxylic acid{3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide

Example 20 was synthesized from Intermediate 1 via the process of Scheme3, supra, as follows:

To a solution of 6-methyl-pyridine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide (Intermediate 1, 20 mg, 0.07 mmol) in DCM(5 mL) was added DIEA (30 mg, 0.2 mmol) and1-methyl-1H-pyrazole-3-carbonyl chloride (20 mg, 0.1 mmol, MaybridgeChemical Co., Cornwall, UK). After stirring at room temperature for 16h, the reaction mixture was partitioned into dichloromethane andsaturated sodium bicarbonate. The organic layer was dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified on a RP-HPLC/MS purification system (Gradient: acetonitrile inwater, 25-95%, in 3.9 minutes with a cycle time of 5 min. Flow rate: 100mL/min. Mobile phase additive: 25 mM of ammonium formate. Column:Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan))to afford 10 mg (30%) of the title compound,6-methyl-pyridine-2-carboxylic acid{3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide, as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, br, 1H), 7.95 (d, J=7.7Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.26-7.21 (m,1H), 6.76-6.72 (m, 2H), 3.89 (s, 3H), 2.55 (s, 3H), 2.54-2.52 (m, 2H),2.35-2.08 (m, 10H), 1.72-1.69 (m, 2H). ESI-MS m/z: 394.1 (M+H)⁺.

In an analogous manner to Example 20, Examples 21-57 in Table 1 (below)were made from commercially available aryl, heteroaryl or aliphaticcarboxylic acids, or aryl, heteroaryl or aliphatic carbonyl chlorides on0.05-7.0 mmol reaction scales.

In an analogous manner to Example 20, Examples 114-130, 132-139 and 142in Table 1 (below) were made from commercially available aryl,heteroaryl or aliphatic carboxylic acids, or aryl, heteroaryl oraliphatic carbonyl chlorides.

In an analogous manner to Example 20, Examples 131 and 141 in Table 1(below) were made from 4-trifluoromethyl-pyrimidine-2-carboxylic acid(Intermediate 11) and 4-methyl-pyrimidine-2-carboxylic acid(Intermediate 12).

Example 58 6-Methyl-pyrazine-2-carboxylic acid{3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide

Example 58 was synthesized from Intermediate 2 via the process of Scheme3, supra, as follows:

To a round bottom flask was added pyridine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide (3.10 g, 11.0 mmol, Intermediate 2),6-methylpyrazine-2-carboxylic acid (1.83 g, 13.3 mmol; RihaChcm,Kostalov, Czech Republic) and methylene chloride (120 mL). To thesolution was then added PyBOP® (6.90 g, 13.3 mmol) followed bytriethylamine (3.85 mL, 27.6 mmol) and the reaction was stirred for twohours at room temperature. The reaction was transferred to a 500-mLseparatory funnel with methylene chloride (50 mL) and saturated aqueoussodium bicarbonate (150 mL), and extracted with methylene chloride. Theorganic layer was separated and the aqueous layer was extracted againwith methylene chloride (2×75 mL). The combined organic layers werewashed with brine (150 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified on aRP-HPLC/MS purification system (Gradient: acetonitrile in water, 27-95%,in 3.5 min with a shallow gradient from 30-60% between 0.75-3.4 min anda cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 38mM of ammonium acetate. Column: Inertsil® C8, 30×50 mm, 5 μm particlesize (GL Sciences, Tokyo, Japan). Mobile phase and column temperature:50° C.). Fractions were then concentrated under reduced pressure toremove most of the acetonitrile, the resulting aqueous layer was madebasic with solid sodium carbonate (pH>10) and the aqueous layer wasextracted with ethyl acetate (3×200 mL). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford 3.21 g (74%) of the titlecompound, 6-methyl-pyrazine-2-carboxylic acid{3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide, as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 9.17 (s, 1H), 8.58 (s, 1H), 8.54-8.50(m, 1H), 8.17 (dt, J=7.8, 1.0 Hz, 1H), 8.06 (br s, 1H), 7.85 (td, J=7.7,1.7 Hz, 1H), 7.77 (br s, 1H), 7.42 (ddd, J=7.6, 4.8, 1.3 Hz, 1H),2.61-2.57 (m, 5H), 2.40-2.28 (m, 4H), 2.27-2.19 (m, 2H), 2.18-2.08 (m,4H), 1.78-1.68 (m, 2H). ESI-MS m/z: 392.0 (M+H)⁺.

In an analogous manner to Example 58, Examples 59-92 in Table 1 (below)were made from commercially available aryl, heteroaryl or aliphaticcarboxylic acids, or aryl, heteroaryl or aliphatic carbonyl chlorides on0.05-0.5 mmol reaction scales.

In an analogous manner to Example 58, Examples 105-111 in Table 1(below) were made from commercially available aryl, heteroaryl oraliphatic carboxylic acids, or aryl, heteroaryl or aliphatic carbonylchlorides.

In an analogous manner to Example 58, Example 113 in Table 1 (below) wasmade from 4-trifluoromethyl-pyrimidine-2-carboxylic acid (Intermediate11).

In a similar manner to Example 58, Example 93-104 in Table 1 (below)were made from Intermediate 3,N-(3-amino-adamantan-1-yl)-3-fluoro-benzamide, and commerciallyavailable heteroaryl carboxylic acids on 0.05-0.5 mmol reaction scales.

In a similar manner to Example 58, Example 182 and 184 were made fromIntermediate 3, N-(3-amino-adamantan-1-yl)-3-fluoro-benzamide, and4-methyl-pyrimidine-2-carboxylic acid (Intermediate 12) and4-trifluoromethyl-pyrimidine-2-carboxylic acid (Intermediate 11),respectively.

In a similar manner to Example 58, Example 183 in Table 1 (below) wasmade from Intermediate 3, N-(3-amino-adamantan-1-yl)-3-fluoro-benzamide,and a commercially available heteroaryl carboxylic acid.

In a similar manner to Example 58, Examples 145-179 in Table 1 (below)were made from Intermediate 8,6-methyl-pyrazine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide, and commercially available aryl orheteroaryl carboxylic acids, while Example 181 in Table 1 (below) wasmade from Intermediate 8 and 4-trifluoromethyl-pyrimidine-2-carboxylicacid (Intermediate 11).

In a similar manner to Example 58, Examples 185-188 in Table 1 (below)was made from Intermediate 7, pyrazine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide, and commercially available heteroarylcarboxylic acids; Example 1.89 and was made from the Intermediate 7 and4-methyl-pyrimidine-2-carboxylic acid (Intermediate 12).

In a similar manner to Example 58, Examples 191-193 in Table 1 (below)were made from Intermediate 10,2-methyl-pyrimidine-4-carboxylic acid(3-amino-adamantan-1-yl)-amide, and commercially available5-fluoro-pyridine-2-carboxylic acid (Beta Pharm, Inc., New Haven, Conn.,USA), 4-trifluoromethyl-pyrimidine-2-carboxylic acid (Intermediate 11)or 4-methyl-pyrimidine-2-carboxylic acid (Intermediate 12).

In a similar manner to Example 58, Examples 194-196 in Table 1 (below)were made from Intermediate 9, pyrimidine-4-carboxylic acid(3-amino-adamantan-1-yl)-amide, and 4-methyl-pyrimidine-2-carboxylicacid (Intermediate 12), commercially available5-fluoro-pyridine-2-carboxylic acid or4-trifluoromethyl-pyrimidine-2-carboxylic acid (Intermediate 11).

Example 143 6-Methyl-pyridine-2-carboxylic acid{3-[(6-(1-hydroxy-ethyl)-pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide

Example 143 in Table 1 (below) was made from Example 142 via NaBH₄reduction, supra, as follows:

Into a vial containing 6-methyl-pyridine-2-carboxylic acid{3-[(6-acetyl-pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide (50 mg,0.1 mmol, Example 142) in MeOH (2 mL) was added sodium borohydride (6mg, 0.17 mmol) at 0° C. After stirring for 2 h, the reaction mixture wasconcentrated and partitioned into dichloromethane and saturated sodiumbicarbonate. The organic layer was dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified on aRP-HPLC/MS purification system (Gradient: acetonitrile in water, 25-95%,in 3.6 min with a shallow gradient from 33-63% of acetonitrile between0.75-3.3 min and a cycle time of 5 min. Flow rate: 100 mL/min. Mobilephase additive: 48 mM of ammonium formate. Column: Inertsil® C18, 30×50mm, 5 um particle size) to afford 45 mg (90%) of the title compound,6-methyl-pyridine-2-carboxylic acid{3-[(6-(1-hydroxy-ethyl)-pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide.NMR (400 MHz, CDCl₃) δ 8.07-8.00 (m, 2H), 7.90 (d, J=7.9 Hz, 1H), 7.78(t, J=7.9 Hz, 1H), 7.74 (s, b, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.41 (d,J=7.8, Hz, 1H), 7.20-7.06 (m, 1H), 4.91-4.85 (m, 1H), 2.50 (s, b, 5H),2.31-2.26 (m, 2H), 2.21-2.06 (m, 8H), 1.69-1.64 (m, 2H), 1.48 (s, 3H).ESI-MS m/z: 435.0 (M+H)⁺.

Example 144 6-Methyl-pyridine-2-carboxylic acid(3-{[6-(1-hydroxy-1-methyl-ethyl)-pyridine-2-carbonyl]-amino}-adamantan-1-yl)-amide

Example 144 in Table 1 (below) was made from Example 142 via Grignardreaction, supra, as follows:

Into a vial containing 6-methyl-pyridine-2-carboxylic acid{3-[(6-acetyl-pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide (35 mg,0.08 mmol, Example 142) in THF (2 mL) was added 1M methyl lithium (0.4mL) at −40° C. After stirring for 2 h, the reaction mixture was quenchedwith cold water, concentrated and partitioned into dichloromethane andsaturated sodium bicarbonate. The organic layer was dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified on a RP-HPLC/MS purification system (Gradient: acetonitrile inwater, 28-95%, in 3.6 mm with a shallow gradient from 33-60% ofacetonitrile between 0.75-3.4 min and a cycle time of 5 min. Flow rate:100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column:Inertsil® C8, 30×50 mm, 5 um particle size) to afford 25 mg (69%) of thetitle compound, 6-methyl-pyridine-2-carboxylic acid(3-{(6-(1-hydroxy-1-methyl-ethyl)-pyridine-2-carbonyl]-amino}-adamantan-1-yl)-amide.¹H NMR (400 MHz, CDCl₃) δ 8.10-8.06 (m, 2H), 7.95 (d, J=7.6 Hz, 1H),7.86 (t, J=7.8 Hz, 1H), 7.75 (s, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.59 (d,J=7.9 Hz, 1H), 7.26-7.22 (m, 1H), 2.58-2.55 (m, 5H), 2.39-2.13 (m, 10H),1.76-1.71 (m, 2H), 1.59 (s, 6H). ESI-MS m/z: 449.0 (M+H)⁺.

Example 180 2-Trifluoromethyl-pyrimidine-4-carboxylic acid{3-[(6-methyl-pyrazine-2-carbonyl)-amino]-adamantan-1-yl}-amide

Example 180 in Table 1 (below) was made via the process of Scheme 3 fromIntermediate 8 and 2-trifluoromethyl-pyrimidine-4-carboxylic acid, whichwas prepared from the corresponding ester, supra, as follows:

To a microwave vial was added 2-trifluoromethyl-pyrimidine-4-carboxylicacid methyl ester (110 mg, 0.52 mmol, CNH Tech, MA), THF (2 mL), andlithium hydroxide (18 mg, 0.75 mmol) in 200 μL of water. The mixture washeated in a microwave oven for 5 min at 100° C., and then concentratedto dryness under reduced pressure. To the residue was added Intermediate8,6-methyl-pyrazine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide(100 mg, 0.4 mmol), THF (5 mL), DIEA (90 mg, 0.7 mmol) and TBTU (140 mg,0.42 mmol, AKSCI, CA). After stirring at rt for 16 h, the reactionmixture was concentrated and partitioned into DCM and saturated sodiumbicarbonate. The organic layer was separated, dried over sodium sulfate,filtered and concentrated to dryness under reduced pressure. The crudeproduct was purified on a RP-HPLC/MS system (Gradient: acetonitrile inwater, 30-95%, in 3.6 min with a cycle time of 5 min. with a shallowgradient from 40-68% of acetonitrile between 0.75-3.4 min. Flow rate:100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column:Inertsil® C8, 30×50 mm, 5 um particle size) to give 60 mg (40%) of thetitle compound, 2-trifluoromethyl-pyrimidine-4-carboxylic acid{3-[(6-methyl-pyrazine-2-carbonyl)-amino]-adamantan-1-yl}-amide. ¹H NMR(400 MHz, CDCl₃) δ 9.16 (s, 1H), 9.12 (d, J=5.0, 1H), 8.6 (s, 1H), 8.28(d, J=5.0, 1H), 7.80-7.75 (m, 2H), 2.6 (s, b, 5H), 2.42-2.36 (m, 2H),2.23-2.17 (m, 8H), 1.77-1.73 (m, 2H). ESI-MS m/z: 460.9 (M+H)⁺.

In a similar manner to Example 180, Examples 112, 140 and 190 in Table 1(below) were made from Intermediate 2, pyridine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide, Intermediate1,6-methyl-pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide,and Intermediate 7, pyrazine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide, respectively.

TABLE 1 EXAMPLE STRUCTURE CHEMICAL NAME 1

N,N′-(1,3- adamantylene)bis(6-methyl- pyridine-2-carboxamide) 2

N,N′-(1,3- adamantylene)bis(2- pyridinecarboxamide) 3

N,N′-(1,3- adamantylene)bis(3-chloro- benzamide) 4

N,N′-(1,3- adamantylene)bis(4- pyridinecarboxamide) 5

N,N′-(1,3- adamantylene)bis(3-cyano- benzamide) 6

Pyridine-2-carboxylic acid[3-(3-chloro- benzoylamino)-adamantan-1-yl]-amide 7

Pyridine-2-carboxylic acid[3-(3-cyano- benzoylamino)-adamantan-1-yl]-amid 8

Pyridine-2-carboxylic acid {3-[(1-methyl-thiophen- 2-yl-1H-pyrazole-3-carbonyl)-amino]- adamantan-1-yl]-amide 9

Pyridine-2-carboxylic acid {3-[(5-furan-2-yl-1-methyl-1H-pyrazole-3-carbonyl)- amino]-adamantan-1-yl}- amide 10

2-Methyl-2H-indazole-3- carboxylic acid {3- [(pyridine-2-carbonyl)-amino]-adamantan-1-yl}- amide 11

N,N′-(1,3-adamantylene)bis(4- methyl-pyridine-2- carboxamide) 12

N,N′-(1,3- adamantylene)bis(quinoline-2- carboxamide) 13

N,N′-(1,3- adamantylene)bis(quinoxaline- 2-carboxamide) 14

N,N′-(1,3- adamantylene)bis(thiophene- 2-carboxamide) 15

N,N′-(1,3-adamantylene)bis(3- fluorobenzamide) 16

N,N′-(1,3-adamantylene)bis(3- methylbenzamide) 17

N,N′-(1,3-adamantylene)bis(1- methyl-1H-pyrazole-3- carboxamide) 18

5-Methyl-pyrazine-2-carboxylic acid {3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]- adamantan-1-yl}-amide 19

Thiazole-2-carboxylic acid {3- [(1-methy-1H-pyrazole-3-carbonyl)-amino}-adamantan- 1-yl}-amide 20

6-Methyl-pyridine-2-carboxylic acid {3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]- adamantan-1-yl}-amide 21

6-Methyl-pyrazine-2-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 22

6-Morpholin-4-yl-pyridine-2- carboxylic acid-{3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 23

6-Trifluoromethyl-pyridine-2- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 24

Pyridazine-3-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 25

6-Cyanomethyl-pyridine-2- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 26

6-Methyl-pyridine-2-carboxylic acid {3-[(5-cyclopropyl-isoxazole-3-carbonyl)-amino]- adamantan-1-yl}-amide 27

[1,8]Naphthyridine-2- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 28

4-Methyl-pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 29

6-Methyl-pyridine-2-carboxylic acid {3-[(2-methyl-oxazole-4-carbonyl)-amino]-adamantan- 1-yl}-amide 30

6-Methyl-pyridine-2-carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan-1- yl]-amide 31

6-Methyl-pyridine-2-carboxylic acid {3-[(isoxazole-5-carbonyl)-amino]-adamantan- 1-yl}-amide 32

6-Methyl-pyridine-2-carboxylic acid [3-(3-cyano-benzoylamino)-adamantan-1- yl]-amide 33

6-Methyl-pyridine-2-carboxylic acid {3-[(benzofuran-5-carbonyl)-amino]-adamantan- 1-yl}-amide 34

Quinoxaline-2-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 35

Pyrimidine-4-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 36

Benzothiazole-2-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 37

1-Methyl-1H-indazole-3- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 38

6-Methyl-pyridine-2-carboxylic acid {3-{(2,3-dihydro-thieno[3,4-b][1,4]dioxine-5- carbonyl)-amino]-adamantan- 1-yl}-amide 39

6-Methyl-pyridine-2-carboxylic acid {3-[(5-methyl-isoxazole-3-carbonyl)-amino]-adamantan- 1-yl}-amide 40

6-Methyl-pyridine-2-carboxylic acid {3-[(thiazole-2-carbonyl)-amino]-adamantan-1-yl}- amide 41

Pyrazine-2-carboxylic acid {3- [(6-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 42

6-Methyl-pyridine-2-carboxylic acid {3-[(1-ethyl-1H-pyrazole-3-carbonyl)-amino]- adamantan-1-yl}-amide 43

6-Methyl-pyridine-2-carboxylic acid [3-(3-methoxy-benzoylamino)-adarnantan-1- yl]-amide 44

6-Methyl-pyridine-2-carboxylic acid [3-(3-pyrimidin-2-yl-benzoylamino)-adamantan-1- yl]-amide 45

6-Methyl-pyndine-2-carboxylic acid [3-(3-chloromethyl-benzoylamino)-adamantan-1- yl]-amide 46

6-Methyl-pyridine-2-carboxylic acid [3-(cyclobutanecarbonyl-amino)-adamantan-1-yl]- amide 47

6-Methyl-pyridine-2-carboxylic acid {3-[(3,3-difluoro-cyclobutanecarbonyl)-amino]- adamantan-1-yl}-amide 48

6-Methyl-pyridine-2-carboxylic acid {3-[(2-methyl-cyclopropanecarbonyl)- amino]-adamantan-1-yl}- amide 49

2-Methyl-2H-indazole-3- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 50

6-Chloro-imidazo[1,2- a]pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 51

Imidazo[1,2-a]pyridine-7- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 52

Imidazo[1,2-a]pyridine-2- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 53

Imidazo[1,2-a]pyridine-6- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 54

6-Methyl-imidazo[1,2- a]pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 55

5-Methyl-imidazo[1,2- a]pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 56

7-Methyl-imidazo[1,2- a]pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 57

6-Chloro-pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 58

6-Methyl-pyrazine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}- amide 59

Pyridine-2-carboxylic acid [3- (3-fIuoro-benzoylamino)-adamantan-1-yl]-amide 60

Pyrimidine-4-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}- amide 61

6-Pyrrolidin-1-yl-pyridine-2- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 62

Benzo[c]isoxazole-3- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 63

5-Methyl-pyrazine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}- amide 64

Pyridine-2,6-dicarboxylic acid 2-methylamide 6-({3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide) 65

2-Methyl-benzoxazole-6- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 66

1H-Pyrrolo[3,2-b]pyridine-5- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 67

2,3-Dihydro-1H-indole-5- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 68

6-Methoxy-pyridine-2- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 69

1-Methyl-1H-indole-5- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 70

6-{3-[(Pyridine-2-carbonyl)- amino]-adamantan-1-yl-carbamoyl}-3,4-dihydro-1H- isoquinoline-2-carboxylic acid tert-butylester 71

Pyridine-2-carboxylic acid (3- benzoylamino-adamantan-1- yl)-amide 72

6-Methyl-pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}- amide 73

Pyridine-2-carboxylic acid {3- [(5-methyl-isoxazole-3-carbonyl)-amino]-adamantan- 1-yl}-amide 74

Pyridine-2-carboxylic acid {3- [(thiazole-2-carbonyl)-amino]-adamantan-1-yl}-amide 75

Pyridine-2-carboxylic acid {3- [(thiophene-2-carbonyl)-amino]-adamantan-1-yl}- amide 76

Pyridine-2-carboxylic acid {3- [(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan- 1-yl}-amide 77

Pyridine-2-carboxylic acid {3- [(isoxazole-5-carbonyl)-amino]-adamantan-1-yl}- amide 78

Pyridine-2-carboxylic acid {3- [(3-methyl-isoxazole-5-carbonyl)-amino]-adamantan- 1-yl}-amide 79

2-Methyl-2H-indazole-3- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 80

Pyridine-2-carboxylic acid [3- (3-methoxy-benzoylamino)-adamantan-1-yl]-amide 81

Pyridine-2-carboxylic acid [3- (4-methoxy-benzoylamino)-adamantan-1-yl]-amide 82

Pyridine-2-carboxylic acid [3- (cyclobutanecarbonyl-amino)-adamantan-1-yl]-amide 83

Pyridine-2-carboxylic acid {3- [(2,2-difluoro- cyclopropanecarbonyl)-amino]-adamantan-1-yl}- amide 84

Pyridine-2-carboxylic acid [3- (cyclohexanecarbonyl-amino)-adamantan-1-yl]-amide 85

Pyridine-2-carboxylic acid [3- (cyclopentanecarbonyl-arnino)-adamantan-1-yl]- amide 86

6-Chloro-imidazo[1,2- a]pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 87

Imidazo[1,2-a]pyridine-7- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 88

Imidazo[1,2-a]pyridine-2- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 89

Imidazo[1,2-a]pyridine-6- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 90

6-Methyl-imidazo[1,2- a]pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 91

7-Methyl-imidazo[1,2- a]pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 92

5-Methyl-imidazo[1,2- a]pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 93

Pyrimidine-4-carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan-1-yl]-amide 94

5-Methyl-pyrazine-2-carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan-1- yl]-amide 95

Pyrazine-2-carboxylic acid [3- (3-fluoro-benzoylamino)-adamantan-1-yl]-amide 96

6-Methyl-pyrazine-2-carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan-1- yl]-amide 97

1-Methyl-1H-pyrazole-3- carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan-1- yl]-amide 98

6-Chloro-imidazo[1,2- a]pyridine-2-carboxylic acid {3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 99

Imidazo[1,2-a]pyridine-7- carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan-1- yl]-amide 100

Imidazo[1,2-a]pyridine-2- carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan-1- yl]-amide 101

Imidazo[1,2-a]pyridine-6- carboxylic acid [3-(3-fIuoro-benzoylamino)-adamantan-1- yl]-amide 102

6-Methyl-imidazo[1,2- a]pyridine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 103

5-Methyl-imidazo[1,2- a]pyridine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 104

7-Methyl-imidazo[1,2- a]pyridine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 105

Pyrazine-2-carboxylic acid {3- [(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide 106

2,6-Dimethyl-pyrimidine-4- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1- yl}-amide 107

2-Methyl-pyrimidine-4-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide 108

4-Fluoro-pyridine-2-carboxylic acid{3-((pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide 109

Pyridine-2-carboxylic acid {3- [(1,5-dimethyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1- yl}-amide 110

Pyridine-2-carboxylic acid {3-[(2- methyl-thiazole-4-carbonyl)-amino]-adamantan-1-yl}-amide 111

5-Fluoro-pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide 112

2-Trifiuoromethyl-pyrimidine-4- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1- yl}-amide 113

4-Trifluoromethyl-pyrimidine-2 carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1- yl}-amide 114

6-Methyl-pyridine-2-carboxylic acid [3-(3-dimethylamino-benzoylamino)-adamantan-1- yl]-amide 115

6-Methyl-pyridine-2-carboxylic acid {3-[(pyridine-3-carbonyl)-amino]-adamantan-1-yl}- amide 116

6-Methyl-pyridine-2-carboxylic acid {3-[(pyridine-4-carbonyl)-amino]-adamantan-1-yl}- amide 117

6-Methyl-pyridine-2-carboxylic acid {3-[(6-aminopyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 118

2,6-Dimethyl-pyrimidine-4- carboxylic acid {3-[(6-methylpyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 119

2-Methyl-pyrimidine-4- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 120

6-Methyl-pyridine-2-carboxylic acid {3-[(thiazole-4-carbonyl)-amino]-adamantan-1-yl}- amide 121

Pyrimidine-2-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 122

Benzoxazole-5-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 123

[1,6]Naphthyridine-2- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 124

6-Methyl-pyridine-2-carboxylic acid {3-[(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)- amino]-adamantan-1-yl}- amide 125

6-Methyl-pyridine-2-carboxylic acid {3-[(4-fluoropyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 126

4,6-Dimethyl-pyridine-2- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 127

6-Methyl-pyridine-2-carboxylic acid {3-[(1,5-dimethyl-1H-pyrazole-3-carbonyl)-amino]- adamantan-1-yl}-amide 128

6-Methyl-pyridine-2-carboxylic acid {3-[(4-methoxypyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 129

6-Methyl-pyridine-2-carboxylic acid {3-[(3-fluoropyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 130

6-Methyl-pyridine-2-carboxylic acid {3-[(5-methylpyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 131

4-Trifluoromethyl-pyrimidine-2- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 132

6-Methyl-pyridine-2-carboxylic acid {3-[(4-hydroxypyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 133

Pyridine-2,6-dicarboxylic acid 2-amide 6-({3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide) 134

6-Methyl-pyridine-2-carboxylic acid {3-[(6- hydroxymethylpyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 135

6-Methyl-pyridine-2-carboxylic acid {3-[(6-fluoropyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 136

6-Methyl-pyridine-2-carboxylic acid {3-[(2-methyl-thiazole-4-carbonyl)-amino]-adamantan- 1-yl}-amide 137

5-Fluoro-pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 138

6-Methyl-pyridine-2-carboxylic acid {3-[(4-bromopyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 139

6-{3-[(6-Methyl-pyridine-2- carbonyl)-amino]-adamantan-1-ylcarbamoyl}-pyridine-2- carboxylic acid methyl ester 140

2-Trifluoromethyl-pyrimidine-4- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 141

4-Methyl-pyrimidine-2- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 142

6-Methyl-pyridine-2-carboxylic acid {3-[(6-acetylpyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 143

6-Methyl-pyridine-2-carboxylic acid (3-[(6-(1-hydroxy-ethyl)-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 144

6-Methyl-pyridine-2-carboxylic acid {3-[(6-(1-hydroxy-1-methyl-ethyl)-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 145

N,N′-(1,3-adamantylene)bis(6- methyl-pyrazine-2- carboxamide) 146

6-Methyl-pyrazine-2-carboxylic acid [3-(3-methoxy-benzoylamino)-adamantan-1- yl]-amide 147

6-Methyl-pyrazine-2-carboxylic acid [3-(3-ethoxy-benzoylamino)-adamantan-1- yl]-amide 148

6-Methyl-pyrazine-2-carboxylic acid [3-(2,5-difluoro-benzoylamino)-adamantan-1- yl]-amide 149

6-Methyl-pyrazine-2-carboxylic acid [3-(3-chloro-4-fluoro-benzoylamino)-adamantan-1- yl]-amide 150

6-Methyl-pyrazine-2-carboxylic acid [3-(2-fluoro-3-trifluoromethyl-benzoylamino)- adamantan-1-yl]-amide 151

6-Methyl-pyrazine-2-carboxylic acid {3-[(6-methoxy-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 152

6-Methyl-pyrazine-2-carboxylic acid [3-(3-chloro-2-fluoro-benzoylamino)-adamantan-1- yl]-amide 153

6-Methyl-pyrazine-2-carboxylic acid {3-[(4-methoxy-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 154

6-Methyl-pyrazine-2-carboxylic acid {3-[(2-methoxy-pyridine-4-carbonyl)-amino]- adamantan-1-yl}-amide 155

6-Methyl-pyrazine-2-carboxylic acid {3-[(2-ethoxy-pyridine-4-carbonyl)-amino]-adamantan- 1-yl}-amide 156

6-Methyl-pyrazine-2-carboxylic acid {3-[(2-methyl-pyridine-4-carbonyl)-amino]-adamantan- 1-yl}-amide 157

6-Methyl-pyrazine-2-carboxylic acid {3-[(2-methyl-thiazole-4-carbonyl)-amino]-adamantan- 1-yl}-amide 158

6-Methyl-pyrazine-2-carboxylic acid [3-(3-fluoro-5-methyl-benzoylamino)-adamantan-1- yl]-amide 159

6-Methyl-pyrazine-2-carboxylic acid [3-(4-fluoro-3-methoxy-benzoylamino)-adamantan-1- yl]-amide 160

6-Methyl-pyrazine-2-carboxylic acid {3-[(2-fluoro-pyridine-4-carbonyl)-amino]-adamantan- 1-yl}-amide 161

6-Methyl-pyrazine-2-carboxylic acid [3-(5-chloro-2-fluoro-benzoylamino)-adamantan-1- yl]-amide 162

6-Methyl-pyrazine-2-carboxylic acid [3-(3-difluoromethoxy-benzoylamino)-adamantan-1- yl]-amide 163

6-Methyl-pyrazine-2-carboxylic acid [3-(3-chloro-5-fluoro-benzoylamino)-adamantan-1- yl]-amide 164

6-Methyl-pyrazine-2-carboxylic acid {3-[(6-fluoro-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 165

6-Methyl-pyrazine-2-carboxylic acid {3-[(5-methyl-pyridine-3-carbonyl)-amino]-adamantan- 1-yl}-amide 166

6-Methyl-pyrazine-2-carboxylic acid [3-(4-fluoro-3-methyl-benzoylamino)-adamantan-1- yl]-amide 167

6-Methyl-pyrazine-2-carboxylic acid [3-(2-fluoro-3-methoxy-benzoylamino)-adamantan-1- yl]-amide 168

6-Methyl-pyrazine-2-carboxylic acid {3-[(3-methyl-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 169

6-Methyl-pyrazine-2-carboxylic acid [3-(2-fluoro-5trifluoromethyl-benzoylamino)- adamantan-1-yl]-amide 170

6-Methyl-pyrazine-2-carboxylic acid {3-[(5-chloro-pyridine-3-carbonyl)-amino]-adamantan- 1-yl}-amide 171

6-Methyl-pyrazine-2-carboxylic acid {3-[(4-fluoro-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 172

Pyrimidine-2-carboxylic acid {3-[(6-methyl-pyrazine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 173

2-Methyl-pyrimidine-4- carboxylic acid {3-[(6-methyl-pyrazine-2-carbonyl)-amino]- adamantan-1-yl}-amide 174

[1,6]Naphthyridine-2- carboxylic acid {3-[(6-methyl-pyrazine-2-carbonyl)-amino]- adamantan-1-yl}-amide 175

Benzoxazole-5-carboxylic acid {3-[(6-methyl-pyrazine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 176

6-Methyl-pyrazine-2-carboxylic acid {3-[(4-bromo-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 177

6-Methyl-pyrazine-2-carboxylic acid [3-(4-fluoro-benzoylamino)-adamantan-1- yl]-amide 178

6-Methyl-pyrazine-2-carboxylic acid {3-[(2-bromo-pyridine-4-carbonyl)-amino]-adamantan- 1-yl}-amide 179

6-Methyl-pyrazine-2-carboxylic acid {3-[(5-fluoro-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 180

2-Trifluoromethyl-pyrimidine-4- carboxylic acid {3-[(6-methyl-pyrazine-2-carbonyl)-amino]- adamantan-1-yl}-amide 181

4-Trifluoromethyl-pyrimidine-2- carboxylic acid {3-[(6-methyl-pyrazine-2-carbonyl)-amino]- adamantan-1-yl}- amide 182

4-Methyl-pyrimidine-2- carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan- 1-yl]-amide 183

2-Methyl-pyrimidine-4- carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan-1- yl]-amide 184

4-Trifluoromethyl-pyrimidine-2- carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan-1- yl]-amide 185

Pyrazine-2-carboxylic acid {3- [(5-fluoro-pyridine-2-carbonyl)-amino]-adamantan-1-yl}- amide 186

Pyrazine-2-carboxylic acid {3- [(2-bromo-pyridine-4-carbonyl)-amino]-adamantan- 1-yl}-amide 187

Pyrazine-2-carboxylic acid {3- [(2-methyl-thiazole-4-carbonyl)-amino]-adamantan- 1-yl}-amide 188

Pyrazine-2-carboxylic acid {3- [(5-cyclopropyl-2H-pyrazole-3-carbonyl)-amino]-adamantan- 1-yl}-amide 189

4-Methyl-pyrimidine-2- carboxylic acid {3-[(pyrazine-2-carbonyl)-amino]- adamantan-1-yl}-amide 190

2-Trifluoromethyl-pyrimidine-4- carboxylic acid {3-[(pyrazine-2-carbonyl)-amino]- adamantan-1-yl}-amide 191

2-Methyl-pyrimidine-4- carboxylic acid {3-[(5-fluoro-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 192

4-Trifluoromethyl-pyrirnidine-2- carboxylic acid {3-[(2-methyl-pyrimidine-4-carbonyl)-amino]- adamantan-1-yl}-amide 193

2-Methyl-pyrimidine-4- carboxylic acid {3-[(4-methyl-pyrimidine-2-carbonyl)-amino]- adamantan-1-yl}-amide 194

4-Methyl-pyrimidine-2- carboxylic acid {3-[(pyrimidine-4-carbonyl)-amino]- adamantan-1-yl}-amide 195

Pyrimidine-4-carboxylic acid {3-[(5-fluoro-pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 196

4-Trifluoromethyl-pyrimidine-2- carboxylic acid {3-[(pyrimidine-4-carbonyl)-amino]- adamantan-1-yl}-amide

Example 197 6-Morpholin-4-yl-pyridine-2-carboxylic acid{3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide

Example 197 in Table 2 (below) was synthesized from Intermediate 4 viathe process of Scheme 7, supra, as follows:

To a microwave vial was added a stir bar, 6-chloro-pyridine-2-carboxylicacid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide(Intermediate 4, 20 mg, 0.05 mmol), DMA (1.0 mL), morpholine (0.05 mL)and cesium carbonate (60 mg, 0.15 mmol). The mixture was heated at 180°C. under microwave irradiation for 15 minutes.

The reaction mixture was cooled to room temperature. Solvent was removedin a high performance solvent evaporation system HT-4X (Genevac Inc.,supra). The residue was dissolved in DCM (2 mL), washed with aq. 1 NNaOH (2 mL) and water (2×2 mL). After removing the solvent, the residuewas purified on a RP-HPLC/MS purification system (Gradient: acetonitrilein water with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phaseadditive: 25 mM of ammonium acetate. Column: Inertsil® C8, 30×50 mm, 5μm particle size (GL Sciences, Tokyo, Japan)) to afford 1.3 mg of thetitle compound, 6-morpholin-4-yl-pyridine-2-carboxylic acid{3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide. The product wasquality checked (QC) by LC-MS (Gradient: acetonitrile in water, 30-90%,in 1.7 minutes with a cycle time of 2 min. Flow rate: 5.0 mL/min. Mobilephase additive: 30 mM of ammonium formate. Column: Inertsil® C8; 50×4.6mm, 3 μm particle size (GL Sciences, Tokyo, Japan)): Retention time:1.26 min; purity (UV₂₅₄): 95%; ESI-MS m/z: 462.1 (M+H)⁺.

In an analogous manner to Example 197, Examples 198-203 in Table 2(below) were synthesized from Intermediate 4 and commercially availableamines on 0.05-0.3 mmol scales; Examples 204-211 in Table 2 (below) weresynthesized from Intermediate 5 and commercially available amines on a0.05 mmol scale; and Examples 212-219 in Table 2 (below) weresynthesized from Intermediate 6 and commercially available amines on a0.05 mmol scale.

Example 220 6-(3-Methoxy-propylamino)-pyridine-2-carboxylic acid{3-pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide

Example 220 in Table 2 (below) was synthesized from Intermediate 4 viathe process of Scheme 7, supra, as follows:

To a microwave vial was added a stir bar, 6-chloro-pyridine-2-carboxylicacid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide(Intermediate 4, 20 mg, 0.05 mmol), copper (11) oxide (20 mg, 0.2mmole), DMA (1 mL), 3-methoxy-propylamine (0.05 mL) and cesium carbonate(120 mg, 0.3 mmol). The mixture was heated at 230° C. under microwaveirradiation for 30 min. Solvent was removed in Genevac. The residue wasdissolved in DCM (2 mL), washed with aq. 1 N NaOH (2 mL), and water (2×2mL). After removing the solvent, the crude product was purified on aRP-HPLC/MS system (Gradient: acetonitrile in water with a cycle time of5 min. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammoniumacetate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GLSciences, Tokyo, Japan)) to afford 3.9 mg of the title compound,6-(3-methoxy-propylamino)-pyridine-2-carboxylic acid{3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide. The product wasquality checked (QC) by LC-MS (Gradient: acetonitrile in water, 30-90%,in 1.7 minutes with a cycle time of 2 mM. Flow rate: 5.0 mL/min. Mobilephase additive: 30 mM of ammonium formate. Column: Inertsil® C8, 50×4.6mm, 3 μm particle size (GL Sciences, Tokyo, Japan)): Retention time:1.29 min; purity (UV₂₅₄): 94%; ESI-MS m/z: 464.6 (M+H)⁺.

In an analogous manner to Example 220, Examples 219-230 in Table 2(below) were synthesized from Intermediate 4 and commercially availableamines on 0.05-0.3 mmol scales; Examples 231-240 in Table 2 (below) weresynthesized from Intermediate 5 and commercially available amines on a0.05 mmol scale; and Examples 241-252 in Table 2 (below) weresynthesized from Intermediate 6 and commercially available amines on a0.05 mmol scale.

Example 253 6-Imidazol-1-yl-pyridine-2-carboxylic acid{3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide

Example 253 in Table 2 (below) was synthesized from Intermediate 4 viathe process of Scheme 7, supra, as follows:

To a microwave vial was added a stir bar, 6-chloro-pyridine-2-carboxylicacid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide(Intermediate 4, 20 mg, 0.05 mmol), copper (II) acetoacetonate (20 mg),DMA (1 mL), imidazole (50 mg, 0.73 mmol) and cesium carbonate (60 mg,0.15 mmol). The mixture was heated at 180° C. under microwaveirradiation for 15 minutes. Solvent was removed in a high performancesolvent evaporation system HT-4X (Genevac, Inc., supra). The residue wasdissolved in DCM (2 mL), washed with aq. 1 N NaOH (2 mL), and water (2×2mL). After removing the solvent, the residue was purified on aRP-HPLC/MS system (Gradient: acetonitrile in water with a cycle time of5 min. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammoniumacetate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GLSciences, Tokyo, Japan) to afford 4.5 mg of the title compound,6-imidazol-1-yl-pyridine-2-carboxylic acid{3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide. ESI-MS m/z:443.5 (M+H)⁺.

In an analogous manner to Example 253, Examples 254-255 in Table 2(below) were synthesized on a 0.05 mmol reaction scale fromIntermediates 5 and 6, respectively.

TABLE 2 EXAMPLE STRUCTURE CHEMICAL NAME 197

6-Morpholin-4-yl-pyridine-2- carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 198

6-(4-Methyl-piperazin-1-yl)- pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 199

6-(3-Dimethyiamino-pyrrolidin- 1-yl)-pyridine-2-carboxylic acid{3-[(pyridine-2-carbonyl)- amino]-adamantan-1-yl}-amide 200

4-Hydroxy-3,4,5,6-tetrahydro- 2H-[1,2′]bipyridinyl-6′- carboxylic acid{3-[(pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 201

6-(3-Hydroxy-pyrrolidin-1-yl)- pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 202

6-[(2-Hydroxy-ethyl)-methyl- amino]-pyridine-2-carboxylic acid{3-[(pyridine-2-carbonyl)- amino]-adamantan-1-yl}-amide 203

6-(3-Hydroxy-propylamino)- pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 204

6-[(2-Dimethylamino-ethyl)- methyl-amino]-pyridine-2- carboxylicacid{3-[(6-methyl- pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide205

6-(3-Hydroxy-pyrrolidin-1-yl)- pyridine-2-carboxylic acid{3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 206

4-Hydroxy-3,4,5,6-tetrahydro- 2H-[1,2,]bipyridinyl-6′- carboxylicacid{3-[(6-methyl- pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide207

6-[(2-Methoxy-ethyl)-methyl- amino]-pyridine-2-carboxylicacid{3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide208

6-(2-Hydroxy-ethylamino)- pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 209

6-[(2-Hydroxy-ethyl)-methyl- amino]-pyridine-2-carboxylic acid{3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 210

6-(3-Hydroxy-propylamino)- pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 211

6-Morpholin-4-yl-pyridine-2- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 212

6-(2-Hydroxy-ethylamino)- pyridine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 213

6-[(2-Hydroxy-ethyl)-methyl- amino]-pyridine-2-carboxylic acid[3-(3-fluoro- benzoylamino)-adamantan-1- yl]-amide 214

6-(3-Hydroxy-propylamino)- pyridine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 215

6-Morpholin-4-yl-pyridine-2- carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan-1- yl]-amide 216

6-(4-Methyl-piperazin-1-yl)- pyridine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 217

6-(3-Dimethylamino-pyrrolidin- 1-yl)-pyridine-2-carboxylic acid[3-(3-fluoro-benzoyiamino)- adamantan-1-yl]-amide 218

4-Hydroxy-3,4,5,6-tetrahydro- 2H-[1,2′]bipyridinyl-6′- carboxylic acid[3-(3-fluoro- benzoylamino)-adamantan-1- yl]-amide 219

6-(3-Hydroxy-pyrrolidin-1-yl)- pyridine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 220

6-(3-Methoxy-propylamino)- pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 221

6-[(3-Dimethylamino-propyl)- methyl-amino]-pyridine-2- carboxylic acid{3-[(pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 222

6-(2-Dimethylamino- ethylamino)-pyridine-2- carboxylic acid(3-[(pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 223

6-(2-Acetylamino-ethylamino)- pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 224

6-(2-Methoxy-ethylamino)- pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 225

6-[(2-Methoxy-ethyl)-methyl- amino]-pyridine-2-carboxylic acid{3-[(pyridine-2-carbonyl)- amino]-adamantan-1-yl}-amide 226

6-(3-Dimethylamino- propyiamino)-pyridine-2- carboxylic acid{3-[(pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 227

6-[(2-Dimethylamino-ethyl)- methyl-amino]-pyridine-2- carboxylic acid(3-[(pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 228

6-((S)-2-Hydroxymethyl- pyrrolidin-1-yl)-pyridine-2- carboxylic acid{3-[(pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 229

6-((R)-2-Hydroxymethyl- pyrrolidin-1-yl)-pyridine-2- carboxylic acid{3-[(pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 230

6-((S)-2-Carbamoyl-pyrrolidin- 1-yl)-pyridine-2-carboxylic acid{3-[(pyridine-2-carbonyl)- amino]-adamantan-1-yl}-amide 231

6-(3-Methoxy-propylamino)- pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 232

6-(2-Dimethylamino- ethylamino)-pyridine-2- carboxylic acid{3-[(6-methyl- pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 233

6-[(3-Dimethylamino-propyl)- methyl-amino]-pyridine-2- carboxylic acid{3-[(6-methyl- pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 234

6-(2-Acetylamino-ethylamino)- pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 235

6-(2-Methoxy-ethylamino)- pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 236

6-(3-Dimethylamino- propylamino)-pyridine-2- carboxylic acid{3-[(6-methyl- pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 237

6-((S)-2-Hydroxymethyl- pyrrolidin-1-yl)-pyridine-2- carboxylic acid{3-[(6-methyl- pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 238

6-((R)-2-Hydroxymethyl- pyrroIidin-1-yl)-pyridine-2- carboxylic acid{3-[(6-methyl- pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 239

6-((S)-2-Carbamoyl-pyrrolidin- 1-yl)-pyridine-2-carboxylic acid{3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 240

6-(2-Carbamoyl-ethyiamino)- pyridine-2-carboxylic acid {3-[(6-methyl-pyridine-2- carbonyl)-amino]-adamantan- 1-yl}-amide 241

6-(3-Methoxy-propylamino)- pyridine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 242

6-(2-Dimethylamino- ethylamino)-pyridine-2- carboxylic acid[3-(3-fluoro- benzoylamino)-adamantan-1- yl]-amide 243

6-[(3-Dimethylamino-propyl)- methyl-amino]-pyridine-2- carboxylic acid(3-(3-fluoro- benzoylamino)-adamantan-1- yl]-amide 244

6-(2-Acetylamino-ethylamino)- pyridine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 245

6-(2-Methoxy-ethylamino)- pyridine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 246

6-[(2-Methoxy-ethyl)-methyl- amino]-pyridine-2-carboxylic acid[3-(3-fluoro- benzoylamino)-adamantan-1 - yl]-amide 247

6-(3-Dimethylamino- propylamino)-pyridine-2- carboxylic acid[3-(3-fluoro- benzoylamino)-adamantan-1- yl]-amide 248

6-[(2-Dimethylamino-ethyl)- methyl-amino]-pyridine-2- carboxylic acid[3-(3-fluoro- benzoylamino)-adamantan-1- yl]-amide 249

6-((S)-2-Hydroxymethyl- pyrrolidin-1-yl)-pyridine-2- carboxylic acid[3-(3-fIuoro- benzoylamino)-adamantan-1- yl]-amide 250

6-((R)-2-Hydroxymethyl- pyrrolidin-1-yl)-pyridine-2- carboxylic acid[3-(3-fluoro- benzoylamino)-adamantan-1- yl]-amide 251

6-((S)-2-Carbamoyl-pyrrolidin- 1-yl)-pyridine-2-carboxyIic acid[3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 252

6-(2-Carbamoyl-ethylamino)- pyridine-2-carboxylic acid [3-(3-fIuoro-benzoylamino)- adamantan-1-yl]-amide 253

6-Imidazol-1-yl-pyridine-2- carboxyiic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan- 1-yl}-amide 254

6-lmidazol-1-yl-pyridine-2- carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 255

6-lmidazol-1-yl-pyridine-2- carboxylic acid [3-(3-fluoro-benzoylamino)-adamantan-1- yl]-amide

Examples 256 and 257 in Table 3 (below) were made via Scheme 3 fromIntermediate 8 and commercially available6-(4-fluoro-phenyl)-pyrimidine-4-carboxylic acid and6-phenyl-pyrimidine-4-carboxylic acid, respectively, on a 0.05 mmolscale.

TABLE 3 Example STRUCTURE CHEMICAL NAME 256

6-(4-Fluoro-phenyl)- pyrimidine-4-carboxylic acid {3-[(6-methyl-pyrazine-2-carbonyl)- amino]-adamantan-1-yl}- amide 257

6-Phenyl-pyrimidine-4- carboxylic acid {3-[(6- methyl-pyrazine-2-carbonyl)-amino]- adamantan-1-yl}-amide

4. Hypothetical Compounds of the Invention

In a similar manner to Example 58, Examples 258-279 in Table 4 (below)can be made from aryl or heteroaryl carboxylic acids via the process ofSchemes 3 and 5. Non-commercially available carboxylic acids, such as4-methyl-pyrimidine-2-carboxylic acid, 2-methyl-pyrimidine-4-carboxylicacid, 4-trifluoromethyl-pyrimidine-2-carboxylic acid,2-trifluoromethyl-pyrimidine-4-carboxylic acid,6-trifluoromethyl-pyrazine-2-carboxylic acid, and5-trifluoromethyl-pyrazine-2-carboxylic acid, can be readily made fromcommercially available heteroaryl-chlorides, such as2-chloro-4-methyl-pyrimidine, 4-chloro-2-methyl-pyrimidine,2-chloro-4-trifluoromethyl-pyrimidine,4-chloro-2-trifluoromethyl-pyrimidine,2-chloro-6-trifluoromethyl-pyrazine, and2-chloro-5-trifluoromethyl-pyrazine, via the process of Scheme 11, in asimilar manner to the synthesis of Intermediate11,4-trifluoromethyl-pyrimidine-2-carboxylic acid, and of Intermediate12,4-methyl-pyrimidine-2-carboxylic acid.

Example 280 6-Methyl-pyrazine-2-carboxylic acid{3-[3-(2-hydroxy-ethoxy)-benzoylamino]-adamantan-1-yl}-amide

Example 280 can be made via the process of Scheme 9, supra, as follows:

Step 1: 6-Methyl-pyrazine-2-carboxylic acid[3-(3-methoxy-benzoylamino)-adamantan-1-yl]-amide

6-Methyl-pyrazine-2-carboxylic acid[3-(3-methoxy-benzoylamino)-adamantan-1-yl]-amide can be made fromcustomary amidation of commercially available 3-methoxybenzoic acid andIntermediate 8,6-methyl-pyrazine-2-carboxylic acid(3-amino-adamantan-1-yl)-amide.

Step 2: 6-Methyl-pyrazine-2-carboxylic acid[3-(3-hydroxy-benzoylamino)-adamantan-1-yl]-amide

6-Methyl-pyrazine-2-carboxylic acid[3-(3-hydroxy-benzoylamino)-adamantan-1-yl]amide can be readily made bytreatment of 6-methyl-pyrazine-2-carboxylic acid[3-(3-methoxy-benzoylamino)-adamantan-1-yl]-amide with BBr₃ in DCM.

Step 3′: 6-Methyl-pyrazine-2-carboxylic acid{3-[3-(2-hydroxy-ethoxy)-benzoylamino]-adamantan-1-yl}-amide

Customary Mitsunobu reaction of 6-Methyl-pyrazine-2-carboxylic acid[3-(3-hydroxy-benzoylamino)-adamantan-1-yl]-amide and2-(t-butyldimethylsiloxy)-ethanol, followed by deprotection of thet-butyldimethylsiloxy group by treatment with tetrabutylammoniumfluoride (TBAF) could afford the title compound,6-methyl-pyrazine-2-carboxylic acid{3-[3-(2-hydroxy-ethoxy)-benzoylamino]-adamantan-1-yl}-amide.

Example 281 in Table 4 (below) can be made in a similar manner toExample 280.

Example 282 6-Methyl-pyrazine-2-carboxylic acid{3-[3-(2-hydroxy-2-methyl-propoxy)-benzoylamino]-adamantan-1-yl}-amide

Example 282 can be made from 6-methyl-pyrazine-2-carboxylic acid[3-(3-hydroxy-benzoylamino)-adamantan-1-yl]-amide (step 2, Example 280):

Step 1: 6-Methyl-pyrazine-2-carboxylic acid{3-[3-(2-oxo-propoxy)-benzoylamino]-adamantan-1-yl}-amide

Alkylation of 6-methyl-pyrazine-2-carboxylic acid[3-(3-hydroxy-benzoylamino)-adamantan-1-yl]-amide (step 2, Example 280)with 1-bromo-propan-2-one in DMF under basic conditions, such as Cs₂CO₃at 60° C., could afford the title compound,6-methyl-pyrazine-2-carboxylic acid{3-[3-(2-oxo-propoxy)-benzoyl-amino]-adamantan-1-yl}-amide.

Step 2: 6-Methyl-pyrazine-2-carboxylic acid{3-[(3-(2-hydroxy-2-methylpropoxy)-benzoylamino]-adamantan-1-yl}-amide

Reaction of 6-methyl-pyrazine-2-carboxylic acid{3-[3-(2-oxo-propoxy)-benzoyl-amino]-adamantan-1-yl}-amide with MeMgBrin THF or ether at 0° C. could yield the title compound,6-methyl-pyrazine-2-carboxylic acid{3-[3-(2-hydroxy-2-methylpropoxy)-benzoylamino]-adamantan-1-yl}-amide.

Example 283 in Table 4 (below) can be made in a similar manner toExample 282.

TABLE 4 Hypothetical Compounds EXAMPLE STRUCTURE CHEMICAL NAME 258

6-Methyl-pyridine-2- carboxyiic acid (3- benzoylamino-adamantan-1-yl)-amide 259

Pyridine-2-carboxylic acid [3-(4- dimethylamino- benzoylamino)-adamantan-1-yl]-amide 260

Pyridine-2-carboxylic acid [3-(3-cyano- benzoylamino)-adamantan-1-yl]-amide 261

Pyridine-2-carboxylic acid {3-[(benzofuran-5- carbonyl)-amino]-adamantan-1-yl}-amide 262

Pyridine-2-carboxylic acid {3-[4-(2- dimethylamino-ethoxy)-benzoylamino]- adamantan-1-yl}-amide 263

Pyrimidine-2-carboxylic acid {3-[(pyridine-2- carbonyl)-amino]-adamantan-1-yl}-amide 264

4-Methyl-pyrimidine-2- carboxylic acid {3- [(pyridine-2-carbonyl)-amino]-adamantan-1-yl}- amide 265

6-TrifIuoromethyl- pyrazine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 266

5-Trifluoromethyl- pyrazine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-1-yl)-amide 267

6-Trifiuoromethyl- pyrazine-2-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)- amino]-adamantan-l-yl}- amide 268

5-Trifluorbmethyl- pyrazine-2-carboxylic acid {3-[(6-methyl-pyridine-2-carbonyl)- amino]-adamantan-1-yl}- amide 269

5-Methyl-pyrazine-2- carboxylic acid {3-[(5- fluoro-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 270

6-Trifluoromethyl- pyrazine-2-carboxylic acid {3-[(5-fluoro-pyridine-2-carbonyl)- amino]-adamantan-1-yl}- amide 271

5-Trifluoromethyl- pyrazine-2-carboxylic acid {3-[(5-fluoro-pyridine-2-carbonyl)- amino]-adamantan-1-yl}- amide 272

Pyrimidine-2-carboxylic acid {3-[(5-fluoro- pyridine-2-carbonyl)-amino]-adamantan-1-yl}- amide 273

4-Methyl-pyrimidine-2- carboxylic acid {3-[(5- fluoro-pyridine-2-carbonyl)-amino]- adamantan-1-yl}-amide 274

4-Trifluoromethyl- pyrimidine-2-carboxylic acid {3-[(5-fluoro-pyridine-2-carbonyl)- amino]-adamantan-1-yl}- amide 275

2-Trifiuoromethyl- pyrimidine-4-carboxylic acid {3-[(5-fluoro-pyridine-2-carbonyl)- amino]-adamantan-1-yl}- amide 276

Pyrimidine-2-carboxylic acid [3-(3-fluoro- benzoylamino)-adamantan-1-yl]-amide 277

2-Trifluoromethyl- pyrimidine-4-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 278

6-Trifluoromethyl- pyrazine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 279

5-Trifluoromethyl- pyrazine-2-carboxylic acid [3-(3-fluoro-benzoylamino)- adamantan-1-yl]-amide 280

6-Methyl-pyrazine-2- carboxylic acid {3-[3-(2- hydroxy-ethoxy)-benzoylamino]- adamantan-1-yl}-amide 281

6-Methyl-pyrazine-2- carboxylic acid (3-{[4-(2- hydroxy-ethoxy)-pyridine-2-carbonyl]- amino}-adamantan-1-yl)- amide 282

6-Methyl-pyrazine-2- carboxylic acid {3-[3-(2- hydroxy-2-methyl-propoxy)-benzoylamino]- adamantan-1-yl}-amide 283

6-Methyl-pyrazine-2- carboxylic acid (3-{[4-(2- hydroxy-2-methyl-propoxy)-pyridine-2- carbonyl]-amino}- adamantan-1-yl)-amide

5. Pharmacological Evaluation of Compounds of the Invention

Compounds of the present invention have been tested in vitro and invivo, and can be tested in vitro and in vivo, in the assays as describedbelow.

In vitro Assays

Radioligand Binding Assays

Binding assays were performed as described in [J. A. O'Brien et al. MolPharmacol., 2003, 64, 731-740] with slight modifications. Briefly, afterthawing, the membrane homogenates were resuspended in 50 mM Tris-HCl,0.9% NaCl binding buffer at pH 7.4 to a final assay concentration of 40μg protein/well for [³H] methoxy-5-(2-pyridinylethynyl)pyridine ([³H]MPEP) (American Radiolabeled Chemicals, Inc., St. Louis, Mo.) filtrationbinding. Incubations included 5 nM [³H] MPEP, membranes and eitherbuffer or varying concentrations of compound. Samples were incubated for60 min at room temperature with shaking. Non-specific binding wasdefined with 10 μM MPEP. After incubation, samples were filtered over aGF/C filter (presoaked in 0.25% polyethyleneimine (PEI)) and then washed4 times using a Tomtec® Harvester 96® Mach III cell harvester (Tomtec,Hamden, Conn.) with 0.5 mL ice-cold 50 mM Tris-HCl (pH 7.4).

IC₅₀ values were derived from the inhibition curve and K₁ values werecalculated according to the Cheng and Prusoff equation ofK_(i)=IC₅₀/(1+[L]/K_(d)) described in [Y. Cheng and W. H. PrusoffBiochem. Pharmacol. 1973, 22, 3099-3108] where [L] is the concentrationof radioligand and K_(d) is its dissociation constant at the receptor,derived from the saturation isotherm. The K_(i) value for Examples 1 and2 were 6.7 and 40 nM, respectively. Examples 19, 42, 44, 58, 65, 67, 69,72, 74, 79, 93, 94, 95, 96, 105, 107, 119 and 120, have Ki valuesranging from 6 to 700 nM.

Calcium Mobilization Assay to Test for Negative or Positive AllostericActivity

The cDNA for rat metabotropic glutamate receptor 5 (rmGluR5) was agenerous gift from S. Nakanishi (Kyoto University, Kyoto, Japan). ThermGluR5 was stably expressed in a HEK 293 cell line and grown inDulbecco's Modified Eagle Medium (DMEM) (Invitrogen, Carlsbad, Calif.)with supplements (10% bovine calf serum, 4 mM glutamine, 100 units/mLpenicillin, 100 μg/mL streptomycin and 0.75 mM G1418) at 37° C., 5% CO₂.Twenty-four hours prior to assay, cells were seeded into 384-well blackwall microliter plates coated with poly-D-lysine. Just prior to assay,media was aspirated and cells dye-loaded (25 μL/well) with 3 μMFluo-4/0.01% pluronic acid in assay buffer (Hank's Balanced SalineSolution (HBSS)): 150 mM NaCl, 5 mM KCl, 1 mM CaCl₂, 1 mM MgCl₂, plus 20mM N-2-Hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES), pH 7.4,0.1% bovine serum albumin (BSA) and 2.5 mM probenicid) for 1 hour in 5%CO₂ at 37° C. After excess dye was discarded, cells were washed in assaybuffer and layered with a final volume equal to 30 μL/well. Basalfluorescence is monitored in a fluorometric imaging plate reader (FLIPR)(Molecular Devices, Sunnyvale, Calif.) with an excitation wavelength of488 nm and an emission range of 500 to 560 nm. Laser excitation energywas adjusted so that basal fluorescence readings were approximately10,000 relative fluorescent units. Cells were stimulated with an EC₂₀ oran EC₈₀ concentration of glutamate in the presence of a compound to betested, both diluted in assay buffer, and relative fluorescent unitswere measured at defined intervals (exposure=0.6 sec) over a 3 minperiod at room temperature. Basal readings derived from negativecontrols were subtracted from all samples. Maximum change influorescence was calculated for each well. Concentration-response curvesderived from the maximum change in fluorescence were analyzed bynonlinear regression (Hill equation). A negative modulator can beidentified from these concentration-response curves if a compoundproduces a concentration dependent inhibition of the EC₈₀ glutamateresponse. Exemplified compounds Examples 1-10 were tested in the aboveassay for negative allosteric modulation: FLIPR maximum inhibitionranged 90% to 99% while FLIPR IC₅₀ ranged from 0.9 nM to 1300 nM.Examples 11-163 also were tested in the above assay. For Examples11-104, FLIPR maximum inhibition ranged from 63% to 99%, while FLIPRIC₅₀ ranged from 0.7 nM to 600 nM; and for Examples 105-163, FLIPRmaximum inhibition ranged from 70% to 99%, while FLIPR IC₅₀ ranged from0.7 nM to 1800 nM. Examples 164-178, 181-182, 184-187, 189-194, 196,197-255 were tested in the above assay for negative allostericmodulation: FLIPR maximum inhibition ranged 63% to 99% while FLIPR IC₅₀ranged from 0.4 nM to 1300 nM.

A positive modulator can be identified from these concentration-responsecurves if a compound produces a concentration dependent increase in theEC₂₀ glutamate response. Examples 256-257 exhibited positive modulation,having FLIPR EC₅₀ of 300 nM and 830 nM, and maximum modulation of 170%and 120%, respectively.

In Vivo Assays

Examples 1, 2 and 58 were evaluated in vivo for anxiolytic effects using(1) mouse marble burying (mMB) methods similar to those described in [K.Njung'e, K. and S. L. Handley, Pharmacology, Biochemistry and. Behavior,1991, 38, 63-67] and (2) a modified Geller-Seifter conflict testdescribed in [N. A. Moore et al. Behavioural Pharmacology. 1994, 5,196-202].

More specifically for the rnMB testing, adult; male CD1 mice (CharlesRiver Laboratories (Kingston, N.Y.)), weighing 25 to 30 g, were used.All animals were-group-housed in a standard colony room with a 12:12light/dark cycle (lights on at 6:00 am) for at least one week prior totesting. Food and water were provided ad libitum. Animals were weighed,tail marked, and randomly assigned to treatment groups before testing.

For each test, sixty minutes after the injection of vehicle or testcompound, or 30 min after injection of the positive control, buspirone,mice were individually placed into test cages containing 1.5 in of Aspenbedding (PWI brand) and two rows of 10 marbles (20 marbles per test cagetotal). Filter tops were used to cover each test cage. Thirty minuteslater, mice were removed from test cages and returned to their homecages. The number of fully visible marbles (less than ⅔ covered withbedding) were counted and subtracted from 20 to arrive at the number ofmarbles buried. Twelve mice were tested per group.

Testing included multiple tests with each test performed to evaluatebuspirone hydrochloride (BUS; Sigma Aldrich) (positive control) and/or acompound of the present invention. Each compound was dissolvedimmediately prior to testing in 20% beta-cyclodextrin (compound of thepresent invention) or distilled water (BUS) and administered at one ormore doses (such as 3, 10, and/or 30 mg/kg) via subcutaneous (SC) orintraperitoneal (IP) injection at the indicated pretreatment times(i.e., 30, 60, or 120 min pretreatment). Doses were measured in mg drug(salt form) per kg body weight. Data was analyzed using one-way ANOVAwith post-hoc Dunnett's test.

More specifically for the Geller-Seifter Conflict testing, rodentoperant chambers (ENV-007CT, Med Associates Inc. (Georgia, Vt.)) andsound-attenuating chambers (ENV-018MD, Med Associates Inc.) were used.Each chamber was equipped with a house light, cue lights, grid floor todeliver foot shocks via a programmable shocker, (ENV-414, MedAssociates, Inc.) and food hopper. Two levers were located on eitherside of the food hopper. Rats were trained to only respond on the leftlever. Food reinforcement was used (Dustless Precision Pellets, 45 mg,BioServ, (Frenchtown, N.J.)). MED-PCIV software (Med Associates) wasused to run experimental sessions and collect data.

Prior to beginning the Conflict procedure, animals were initiallytrained to lever press on fixed ratio schedules (FR 1, 2, 5, and 10).Once animals obtained 25 rewards on a FR 10 schedule for 2 consecutivedays, animals began training on a three component Conflict schedule. Thethree components were as follows: (1) an unpunished, variable interval30 s (VI30) schedule of food reinforcement to reinforce lever pressingon a variable time schedule that averaged 30 s; this period had aduration of 9 minutes and was signaled by illumination of the rear houselight only; (2) immediately following was a 3 minute time out period(TO) that was signaled by total darkness; responding was recorded butwas neither rewarded nor punished; (3) a punished, fixed ratio 10 (FR10)schedule of reinforcement that simultaneously presented food and footshock (0.3 mA, 500 ms) on every tenth lever press during a 3 minuteperiod; this component was signaled by illumination of the rear houselight and cue lights above each lever. These three components wererepeated twice in the same order during the daily 30 minute session.

Testing began when stable rates of responding were observed for 5 days(no significant trends up or down). Animals were tested using aLatin-squares design, on Wednesdays and Fridays. Animals served as theirown controls and received all treatments. To maintain baselineperformance, animals were also trained the remaining three weekdays.

Testing was performed using 12 adult, male Sprague-Dawley rats, weighing426-567 g (Charles River Laboratories (Kingston, N.Y.)). Animals werepair-housed in colony rooms maintained at controlled temperature (68-72°F.) and a 12-h light/dark cycle (lights on 06:00). Animals were givenfree access to water, while food was limited to 15 g of Bacon Lover'sTreats (BioServ) after training/testing Monday through Thursday. Fridaythrough Sunday, animals had free access to Lab Diet 5012 Rat Diet (PMINutrition International, LLC, Brentwood, Mo.) until cages were changedand food removed on Sunday.

Testing included multiple tests where each test was performed toevaluate either a reference compound or a compound of the presentinvention. Reference anxiolytics included chlordiazepoxide, diazepam andbuspirone, which were dissolved in saline or water and administered viaSC, IP, and/or PO. Test compounds were dissolved in 20%beta-cyclodextrin, and the pH was adjusted to 7 with NaHCO₃. For eachtest, the compound to be evaluated was tested at one or more doses (suchas 10, 20, 30 and/or 50 mg/kg) via p.o. administration 60 minutes beforethe test using an injection volume of 2 mL/kg in comparison with avehicle control group. Doses were measured in mg drug (salt form) per kgbody weight. Data was analyzed using Repeated Measures ANOVA withpost-hoc Dunnett's test.

Compounds of the invention have significant anxiolytic activity. Forexample, Example 1 showed significant activity in both assays (mMB EDmin3 mg/kg; Geller-Seifter EDmin 10 mg/kg). Example 2 also showedsignificant activity in both assays (mMB EDmin 30 mg/kg, Geller-SeifterEDmin 20 mg/kg). Example 58 showed significant activity in both assays(mMB EDmin 10 mg/kg, SC; Geller-Seifter EDmin 10 mg/kg, PO); and asshown in the following tables.

TABLE 5 Statistically Significant Active Dose(s) of RepresentativeCompounds of the Present Invention in Mouse Marble Burying Assay ActiveDose Statistical Example mg/kg (SC injection) significance⁺ 1 3, 10, 30F(4,55) = 19.6, p < 0.01 2 30 F(4,55) = 7.2, p < 0.01 41 10, 30 F(4,55)= 17, p < 0.01 58 10, 30 F(4,55) = 19, p < 0.01 63 30 F(4,55) = 5.7, p <0.05 93 30 F(4,54) = 6.6, p < 0.01 94 3, 10, 30 F(4,55) = 46, p < 0.0195 10, 30 F(4,55) = 18, p < 0.01 96 10, 30 F(4,55) = 30, p < 0.01 105 30F(4,55) = 11, p < 0.01 107 10 t(22) = 17, p < 0.01 119 10 t(22) = 25, p< 0.01 145 30 F(4,54) = 10, p < 0.01 179 10 t(22) = 6, p < 0.01 183 10t(22) = 4, p < 0.01 185 30 F(4,55) = 15, p < 0.01 191 10, 30 F(4,55) =11, p < 0.01 ⁺Statistical significance was determined using one-wayANOVA with post-hoc Dunnett's test or paired students t-test

TABLE 6 Statistically Significant Active Dose(s) of RepresentativeCompounds of the Present Invention in Geller-Seifter Assay Activedose(s) Statistical Example mg/kg (oral injection) significance⁺ 1 50t(7) = 2.99, p < 0.05 2 20 t(7) = 2.4, p < 0.05 41 30 F(3,7) = 11.6, p <0.01 58 10, 20 F(3,11) = 8, p < 0.05 94 20 F(3,8) = 2.7, p < 0.05 95 10,30 F(3,9) = 5.7, p < 0.05 ⁺Statistical significance was determined usingone-way ANOVA with post-hoc Dunnett's test or paired students t-test

Compounds of the present invention were evaluated in vivo forantidepressive effects. An assessment of depression-like actions wasmeasured using a forced swim test similar to that described in [J. F.Cryan, et al. Neuroscience and Biobehavioral Reviews 2005, 29, 547-569.]Animals used for testing were adult, male NIH Swiss Webster mice (HarlanLaboratories (Frederick, Md.)), weighing 22 to 24 g, which wereacclimatized and housed as previously described with the mice used inthe rnMB tests.

For the mouse Forced Swim Test (mFST), mice were individually placedinto clear Pyrex® cylinders (11 cm diameter, 16.5 cm height) containing11 cm deep tap water (23-25° C.) sixty min after the injection ofvehicle or test compound, or 30 min after injection of the positivecontrol, imipramine hydrochloride (IMI; Sigma Aldrich, St. Louis, Mo.).Imipramine was prepared with isotonic saline and test compounds wereprepared as described previously with mMB tests. Doses used were asdescribed previously with mMB tests. The percentage of time spentfloating, swimming, and struggling (“climbing”) was measured during a 6min session. Swim sessions were video monitored and analyzed inreal-time using the Biobserve Automated FST apparatus and software(Biobserve GmbH, Bonn, Germany). Group size ranged from twelve tothirteen mice. Doses were measured in mg drug (salt form) per kg bodyweight. Data was analyzed using one-way ANOVA with post-hoc Dunnett'stest.

Compounds of the present invention had significant antidepressiveeffects in the mFST at 3 mg/kg, 10 mg/kg, 30 mg/kg, or a combinationthereof (Statistical significance (p<0.05) was determined using one-wayANOVA with post-hoc Dunnett's test.)

An in vivo effect of a compound of the present invention may also beevaluated by using the following, non-limiting, examples of in vivobehavioral animal models. The following behavioral models are notintended as the only models useful for determining the efficacy of acompound of the present invention to treat the corresponding disorder ordisease.

Compounds of the invention also can be evaluated in vivo for anxiolyticeffects using a light-enhanced startle (LES) reflex method as thatdescribed in [Walker and Davis. Biol. Psychiatry, 1997, 42, 461-471].The startle response is a coordinated contraction of skeletal musclegroups in response to a high intensity unexpected stimulus. Most sensorymodalities can be used, but sound is most frequently employed because itis easily controlled. Thus, when a short burst of sufficient intensityoccurs (e.g., 115 dB) an involuntary startle response occurs. High lightlevels increase the startle response in nocturnal species such as therat and this effect does not require any pre-conditioning.Anxiolytics—an agent that relieves anxiety—decrease light-enhancedstartle.

For the LES test, an apparatus consisting of a commercially availablesoundproofed startle chamber (e.g., SR-LAB™ Startle Response System, SanDiego Instruments, San Diego, Calif.) can be used. All experimentalevents and data recording can be controlled by computer program (e.g.,SR-LAB™ control unit). Rats are placed within the startle chamber in asmall Perspex® cylinder, slightly larger than the rat, which is attachedto a base plate containing a strain gauge. Vertical movement of the ratsuch as occurs during a startle response results in deformation of thebase plate, which generates a current in the strain gauge that isproportional to the size of the movement, i.e., the size of the startleresponse. A loudspeaker is placed directly above the rat to providebackground sound and stimuli. A light source (2500-3500 Lux) is locatedin each startle chamber.

The LES test consists of two 20-minute sessions (first with lights offand then with lights on) of which the first 5 minutes are forhabituation, during which background noise of 70 dB intensity isprovided within the chamber. At the end of each habituation period, 10stimulations of 110 dB are presented to habituate the animals.Thereafter, three trial types are presented in pseudo random order, 8times each. Trials are separated by 15-25 seconds. The trial types are100, 105 or 110 dB startle during which a 40 ms burst of white noise at100, 105 or 110 dB is presented, resulting in a startle response. Aperiod of 5 minutes without light or noise separates the two sessions.An appropriate rat species that can be use includes male Rj: Wister(Hans) rats (180-280 g weight at start of the testing with a maximumweight range per test of 50 g) (Elevage Janvier, Le Genest-Saint-Isle,France). The rats should be allowed to acclimatize to laboratoryconditions at least 5 days before testing with free access to food andwater. Acclimatization conditions should be comparable to thosedescribed in the scientific literature and/or known to those skilled inthe art.

The output from the startle platform is recorded for 40 ms starting fromthe onset of the startle stimulus. Three variables are recorded for eachtrial: the average response over the whole recording period, the peakresponse and the time to peak response. The startle intensity iscalculated for each rat by averaging the 8 trials of each type underdark or light conditions and calculating the percentage increase instartle amplitude (average and peak values) caused by light (LES). Thetime to peak response is a measure of reaction time.

The test is performed un-blinded using, e.g., 12 rats per group. Testingincludes multiple tests where each test is performed to evaluate areference compound (e.g., chlordiazepoxide), comparative compound (e.g.,pregabalin) and/or a compound of the present invention. For example, intest 1, a known anxiolytic, such as chlordiazepoxide and pregabalin, isused, followed by test 2 using the mGluR5 antagonist2-methyl-6-(phenylethynyl)-pyridine (MPEP), and then test 3 is performedusing a compound of the present invention. Alternatively, each test canbe performed concurrently, or in some combination of sequentially andconcurrently. For each test, the compound to be evaluated is tested atone or more doses (such as 1, 3, 10, 30 and/or 100 mg/kg) via p.o.administration 60 minutes before the test in comparison with a vehiclecontrol group. Prior to testing, test compounds can be tested forsolubility by cold stirring of the highest intended dose for 10 min indistilled water. If soluble, distilled water can serve as the vehicle.If insoluble, the test compounds can be suspended in 0.2%hydroxypropylmethylcellulose (HPMC) in distilled water. Doses can beprepared as weight to volume (WN) stock solutions and then seriallydiluted (V/V) for compounds in solution or separately weighted (W/V) forcompounds in suspension.

For each test, data is analyzed by comparing treated groups with thevehicle control using unpaired Student's t tests. LES in each group willbe analyzed by comparing within each treated group the intensity ofstartle reaction under dark and light conditions using paired Student'st tests.

The “Vogel Conflict Test” as described by Vogel et al(Psychopharmacologia, 1971, 21, 1-7) can be used to detect anxiolyticactivity of a compound because anxiolytics increase punished drinking.In the test, rats are deprived of water for approximately 48 hours andare then placed individually into a transparent Plexiglas® enclosure(15×32×34 cm) with a floor consisting of stainless steel bars (0.4 cm)spaced 1 cm apart. The back wall of the enclosure is made of opaquePlexiglas® thereby concealing the observer from the experimental animal.In the centre of the opposite wall, 5 cm above the floor, a metal waterspout protrudes into the cage and is connected to one pole of a shockgenerator (Apelex: Type 011346). The other pole of the shock generatoris connected to the metal grid floor.

The rat is left to explore until it finds the water spout. Then, everytime it drinks, it receives a slight electric shock (1.7 mA, 1 s) 2seconds after it starts lapping. The number of punished drinks iscounted during a 3 minute test.

The test is performed blind with, e.g., 10 rats per group. Testingincludes multiple tests using reference compounds and compounds of thepresent invention that are prepared and administered as previouslydescribed LES test. Appropriate animals for testing with acclimatizationconditions are, for example, the male Rj: Wistar (Hans) rats aspreviously described for the LES test. Data is analyzed by comparingtreated groups with appropriate controls using unpaired Student's ttests.

Antidepressive effect can be evaluated using the Flinders Sensitive Line(FSL) rat in the FST and social interaction test as described in [D. H.Overstreet and G. Griebel Pharmacol Biochem Behav., 2005, 82, 1:223-227]. More specifically, compounds of the invention are tested atmultiple doses (e.g., 10 mg/kg, 30 mg/kg, etc.) by preparing in 20%HP-beta-cyclodextrin and against vehicle control. In addition to an FSLvehicle control group, Flinders Resistant Line rats' vehicle controlgroup is tested. Test compounds are administered daily by IP injection(2 mg/kg injection volume) for 14 days. Animals are tested in the socialinteraction and forced swim tests on Day 15, 22-24 hours after theinjection on Day 14, as described in Overstreet and Griebel 2005. Six toeight animals per group are tested.

Anxiolytic and antidepressive effect can also be evaluated using aparadigm for decreased HPA axis feedback (David et al., 2007, SFNmeeting in San Diego). This model based on the chronic delivery ofcorticosterone in the drinking water, causes anxiety- anddepression-like behaviors in mice. The model consists of a sustainedadministration of a high dose (35 μg/mL), but not a low dose (7 μg/mL),of corticosterone for four or seven weeks. Such a treatment inducedanxiety- and depression-like behaviour in C57B16/NTac mouse strain asindicated by a decreased time spent and number of entries into center ofthe arena during the 30 minutes open field test (OF), whereas totalambulation was unaltered. Also, the latency to feed was increased incorticosterone-treated mice submitted to the novelty suppressed feeding(NSF) paradigm. As the corticosterone treatment did not alterfood-intake in the home cage (familiar environment), changes in feedinglatency were not due to changes in appetite or an underlying metabolicabnormality. Importantly, the adrenocorticotropic hormone (ACTH) andcorticosterone (CORT) response to an acute stressor (6 min forced swimtest (FST)), measured as plasma-concentrations, was blunted inC57BL/6NTac mice. Theses results were confirmed in CD1 strain mice.Three weeks treatment with the antidepressant imipramine (40 mg/kg/dayip) and fluoxetine (18 mg/kg/day ip) reversed the anxiety- anddepression-like effects caused by a seven weeks corticosterone treatmentin the OF, NSF and FST.

In such test, 240 adult male mice of C57B1/6Ntac strain (Taconic Farms(Denmark)), 8-10 weeks old, which are allowed to acclimate to thefacility for at least 1 week prior to testing (e.g., 5 per cage under a12 h (06:00-18:00) light-dark cycle at 22° C.) with food and waterfreely available.

A compound of the invention (30 or 60 mg/kg, per day in chow),fluoxetine (18 mg/kg per day in drinking water) or vehicle (0.45%β-cyclodextrine, βCD in drinking water) are administered to mice treatedvia drinking water with either vehicle or corticosterone (35 μg/mL).After 7 weeks of treatment as indicated below, mice are tested in thefollowing behavioral tests: OF, NSF, FST and sucrose splash groomingtest. Treatment is started with either βCD or corticosterone (35 μg/mL)given via the drinking water for 3 weeks (n=200 mice per group).Thereafter, administration with βCD or corticosterone will continue, andmice are divided into 8 groups of 30 mice as indicated below for 4additional weeks.

Week 1-8 Week 3-7 vehicle (βCD) vehicle vehicle (βCD) fluoxetine, 18mg/kg vehicle (βCD) test compound, 30 mg/kg vehicle (βCD) test compound,60 mg/kg 35 μg/mL/day corticosterone vehicle 35 μg/mL/day corticosteronefluoxetine, 18 mg/kg 35 μg/mL/day corticosterone test compound, 30 mg/kg35 μg/mL/day corticosterone test compound, 60 mg/kg

Mice are tested in the behavioral paradigms in this order: OF, NSF,sucrose splash test and then the mouse FST (15 animals/group).

The Open-Field Test

Motor activity is quantified in Plexiglas® open field boxes 43×43 cm²(MED associates, Georgia, Vt.) over a 10 min session. Two sets of 16pulse-modulated infrared photo beams are placed on opposite walls 2.5 cmapart to record x-y ambulatory movements. A 40-W white bulb placed inthe middle of the room provided around 200-lx illumination at floorlevel. Activity chambers are computer interfaced for data sampling at100 ms resolution. The computer defined grid lines that divided eachopen field into center and surrounds regions, with each of four linesbeing 11 cm from each wall. Dependant measures are total time spent inthe center, the numbers of entries into the center and distance traveledin the center divided by total distance traveled. Overall motor activityis quantified as the total distance traveled (cm).

The Novelty-Suppressed Feeding

The novelty suppressed feeding (NSF) is a conflict test that elicitscompeting motivations: the drive to eat and the fear of venturing intothe center of brightly lit arena. Latency to begin eating is used as anindex of anxiety-like behavior because classical anxiolytic drugsdecrease it. The NSF is carried out during a 5-min period as previouslydescribed (Santarelli et al., 2003). Briefly, the testing apparatusconsisted of a plastic box 50×50×20 cm. The floor is covered withapproximately 2 cm of wooden bedding. Twenty-four hours prior tobehavioral testing, all food is removed from the home cage. At the timeof testing, a single pellet of food (regular chow) is placed on a whitepaper platform positioned in the center of the box. An animal is placedin a corner of the maze and a stopwatch is immediately started. Themeasure of interest (chewing) is scored when the mouse is sitting on itshaunches and biting with the use of forepaws. Immediately after thistest, mice are transferred to their home cage and the amount of foodconsumed in 5 min is measured (home cage food consumption). Mice aretested during the light period. Because antidepressants are known tohave various effects on appetite, the feeding drive is assessed byreturning animals in their home cage (familiar environment) immediatelyafter the test. Then, the amount of food consumed over a 5 min-period ismeasured.

Splash Test

The grooming latency is assessed at the end of the corticosteroneregimen (end of seventh week) in the presence or absence of 3-weeks offluoxetine treatment. This test consists in squirting 200 μl of a 10%sucrose solution on the mouse's snout. The grooming frequency is thenrecorded

The mouse Forced Swim Test

A modified forced swim test procedure as described in [Dulawa et al.,Neuropsychopharmcol., 2004, 29, 1321-1330; Holick et al.,Neuropsychopharmcol., 2008, 33, 2: 406-417] is used. Mice are placedindividually into glass cylinders (height: 25 cm, diameter: 10 cm)containing 18 cm water that is maintained at 23-25° C. and videotapingwill be for 6 min via a tripod-mounted camera positioned directly on theside of the cylinder. An increase of swimming and climbing has beenlinked to an activation of serotoninergic and noradrenergic system inrats [see, e.g., Cryan and Lucki, Pharmcol. & Exp. Therap., 2000, 295,3, 1120-1126] and in mice [see, e.g., Dulawa et al. (2004); Holick etal., (2008)], respectively. Therefore, the predominant behavior(swimming, immobility or climbing) is scored here during the last 4 minof the 6 min testing period.

Anxiolytic-like properties also can be evaluated using these additionaltests: (1) social interaction described in [S. E. File and P. Seth,European Journal of Pharmacology, 2003. 463, 35-53], and (2) elevatedplus-maze described in [S. M. Korte and S. F. be Boer European Journalof Pharmacology, 2003, 463, 163-175].

Parkinson's disease (PD) can be assessed by measuring the neurotoxicityof MPTP in rats as described in [E. H. Lee et al. Chin. J. Physiol.,1992, 35, 4: 317-36]. Also experimentally induced striatal DA depletionin animals is a valid model of Parkinsonism, as described in [W. SchultzProg. Neurobiol., 1982, 18, 2-3: 121-66]. The capacity of certainsubstances to damage catecholaminergic neurons has been used extensivelyto produce DA deficiency in animals, as described in [L. E. Annett etal. Exp. Neurol., 1994, 125, 2: 228-46]. PD can also be assessed bymeasuring the neurotoxicity induced by 6-hydroxydopamine (6-OHDA) asdescribed in N. Brcyssc et al. J. Neurosci., 2002, 22, 13: 5669-5678; D.Rylander et al. J. Pharmacol. Exp. Ther., 2009, 330, 1: 227-235; and L.Chen et al. Brain Res., In Press, Uncorrected Proof, available online 21Jun. 2009.doi:10.1016/j.brainres.2009.06.040].

Fragile X Syndrome can be assessed using the fmr1^(tmlCgr) mouse modelas described in [Q. J. Yan et al. Neuropharmacol., 2005, 49, 1053-1066]as well as the Fmr1 knockout mice with a selective reduction in mGluR5expression as described in [G. Dölen et al. Neuron, 2007, 56, 955-962].

Preclinically, animals also can be evaluated for blockade/attenuation ofsymptoms associated with schizophrenia. Positive symptoms in animalmodels of schizophrenia can be evaluated by measuring changes in theoverall level of activity of dopamine (DA) activity with concomitantparallel changes in locomotor activity as described in [R. Depoortere etal. Neuropsychopharmacology, 2003, 28, 11: 1889-902], D-amphetamine(AMPH) and phencyclidine (PCP) via induction of model psychosis orlocomotor hyperactivity as described in [W. J. Freed et al.Neuropharmacology, 1984, 23, 2A: 175-81; F. Sams-DoddNeuropsychopharmacology, 1998 19, 1: 18-25]. For example, Depoortere etal., 2003, have described tests for evaluating locomotor activity,catalepsy, climbing and stereotypy, which relate to positivesymptomology and side effect profile, by characterizing compounds withtypical and atypical antipsychotic efficacy. Attenuation inapomorphine-induced climbing, stereotypy and catalepsy (AIC) can beevaluated as described in [Y. K. Fung et al. Pharmacol. Biochem. Behav.,1986, 24, 1: 139-41 and Y. K. Fung et al. Steroids, 1987, 49, 4-5:287-94]. Additionally, negative symptoms of schizophrenia can beevaluated by measuring social interaction under the influence of NMDAantagonists such as PCP, as described in F. Sams-Dodd, 1998, supra.

Cognitive symptoms of memory, including those from Alzheimer's disease,can be evaluated by such models as the Fear Conditioning Paradigmdescribed in [T. J. Gould et al. Behav. Pharmacol., 2002, 13, 4: 287-94,and A. O. Hamm et al. Brain, 2003, 126, Pt 2: 267-75] and the Radial ArmTest described in [J. P. Aggleton et al. Behav. Brain Res., 1996, 19, 2:133-46], while spatial reference memory and learning can be evaluated inthe Morris watermaze test as described in [Morris. Learn. Motiv., 1981,12, 239-260; B. Bontempi et al. Eur. J. Neurosci. 1996, 8, 11: 2348-60].More specifically, in the Morris watermaze test, a circular water tank(150 cm diameter and 45 cm height) is filled with about 30 cm water andmaintained at 26-28° C. with an escape platform (15 cm diameter) 18 cmfrom the perimeter and always in the same position 1.5 cm beneath thesurface of the water. The water is made opaque by addition of anon-toxic coloring agent (e.g., milk powder) rendering the platforminvisible. Animals are given a single training session over a singleday. The training session consists of 4 consecutive trials in thewatermaze, each separated by 60 seconds. For each trial, the animal isplaced in the watermaze at one of two starting points equidistant fromthe escape platform and allowed to find the escape platform. The animalis left on the escape platform for 60 seconds before starting a newtrial. If the animal does not find the platform within 120 seconds, theanimal is removed from the water and placed on the platform for 60seconds. During the 4 trials, the animals start the watermaze twice fromeach starting point in a randomly determined order per animal.Appropriate animals for testing with acclimatization conditions are, forexample, the male Rj: Wistar (Hans) rats as previously described for theLES test.

The trials are video-recorded and the behavior of animals is analyzedusing a video-tracking system (SMART, Panlab, S. L., Cornelia(Barcelona), Spain). The principal measure taken in each trial is thedistance traveled to find the platform. Secondary measures taken are theswim speed and escape latency. The test is performed blind using, forexample, 12 rats per test group. Testing includes multiple tests usingreference compounds and compounds of the present invention that areprepared and administered as previously described LES test. For eachtest, data is analyzed by comparing treated groups with vehicle controlsusing one-way ANOVA followed by Dunnett's t tests. To increasecomparability with the aforementioned Vogel conflict test, in all tests,rats are subjected to water-deprivation for approximately 24 h beforethe test (Day 1); however, testing is performed in non water-deprivedrats (Day 2).

Additionally, with respect to cognition, memory and hippocampalhypo-functioning can be assessed by measuring the restoration ofsynaptic plasticity in ovariectomized (OVX) female rats as described in[M. Day and M. Good Neurobiol. Learn. Mem., 2005, 83, 1: 13-21].Further, changes in attention function because of schizophrenia can beexamined by the Five (5) Choice Serial Reaction Time Test (5CSRT)described in [J. L. Muir et al. Psychopharmacology (Berl), 1995, 118, 1:82-92 and Robbins et al. Ann. N.Y. Acad. Sci., 1998, 846, 222-37].

Human patients can be evaluated for cognitive diseases or disorders byany of the tests within the skill of those in the art.

Analgesic activity can be evaluated by neuropathic pain model (the“Chung model”) as described in [Kim and Chung, Pain, 1992, 50, 355-363].Tight ligature of spinal nerves in rats is associated with hyperalgesia,allodynia and spontaneous pain, and therefore constitutes a model forperipheral neuropathic pain in humans. Antihyperalgesics reduce thesechronic signs of pain hypersensitivity. Thus, in the Chung model, ratsare anesthetized (sodium pentobarbital 50 mg/kg i.p.) and an incision atthe L4-S2 level is performed to expose the left L5 nerve after cleaningthe flank with chlorhexidine in sprays A cotton thread (standard,non-surgery quality), disinfected with pure alcohol, is placed aroundthe L5 nerve and a simple ligature is tied tightly around the L5 nerve.The wound is then sutured and sprayed with CothiVet® (hydrocotyletincture spray) (Neogen® Corp., Lexington, Ky.). The rats receive a s.c.injection of Clamoxyl (0.67 mL/kg) and are allowed to recover. At least2 weeks after the surgery, when the chronic pain state is fullyinstalled, rats are submitted consecutively to tactile and thermalstimulation of both hindpaws.

For tactile stimulation, the animal is placed under an inverted acrylicplastic box (18×11.5×13 cm) on a grid floor. The tip of an electronicVon Frey probe (Model 1610, BIOSEB, Vitrolles Cedex, France) is thenapplied with increasing force first to the non-lesioned and then thelesioned hindpaw and the force required to induce paw-withdrawal isautomatically recorded. This procedure is carried out 3 times and themean force per paw is calculated.

For heat stimulation, the apparatus (No. 7371, Ugo Basile, Comerio Va.,Italy) consists of individual acrylic plastic boxes (17×11×13 cm) placedupon an elevated glass floor. A rat is placed in the box and left freeto habituate for 10 minutes. A mobile infrared radiant source (96±10mW/cm²) is then focused first under the non-lesioned and then thelesioned hindpaw and the paw-withdrawal latency is automaticallyrecorded. In order to prevent tissue damage, the heat source isautomatically turned off after 45 seconds.

Prior to receiving compound treatment all animals are submitted totactile stimulation of the hindpaws and assigned to treatment groupsmatched on the basis of the pain response of the lesioned hindpaw. Thetest is performed blind using, for example, 10 water-deprived rats pergroup. Appropriate animals for testing are, for example, the male Rj:Wistar (Hans) rats as previously described for the LES test. Testingincludes multiple tests using reference compounds and compounds of thepresent invention. In addition to the pregabalin and MPEP as previouslydescribed for the LES test, duloxetinc can be used as a referencecompound since it is an antihyperalgesic with respect to neuropathicpain associated with diabetes and fibromyalgia. Compounds are preparedand administered as previously described LES test. Testing can beperformed using the same batch of operated rats repeatedly, with aminimum wash-out of 1 week between treatments. Also, to increasecomparability with the aforementioned Vogel conflict test, in all tests,rats are subjected to water-deprivation for approximately 48 hoursbefore each test. For each Chung model test, data will be analyzed bycomparing treated groups with appropriate controls using unpairedStudent's t tests.

Additionally, analgesic/anti-inflammatory activity can be evaluated invivo using the Formalin Paw Test in the mouse such as that described by[Wheeler-Aceto et al, Psychopharmacology, 1991, 104, 35-44). For thetest, mice are given an intraplantar injection of 5% formalin (25 μl)into the posterior left paw. This treatment induces paw licking incontrol animals. The time spent licking is counted for 5 minutes,beginning immediately after injection of formalin (early phase) and for15 minutes starting 15 minutes after injection of formalin (late phase).

The test is performed blind using, e.g., 10 mice per group. Appropriateanimals for testing are, for example, male Rj: NMRI mice (ElevageJanvier), weighing 20-30 g (max. range per experiment=5 g) at thebeginning of testing. Animals are acclimatized as described for theanimals used in the LES test. Testing includes multiple tests usingreference compounds (e.g., morphine), comparative compounds (e.g.,gabapentin and duloxetine), and compounds of the present invention.Compounds of the invention can be evaluated at multiple doses aspreviously described in the LES test, and administered s.c. 60 minutesbefore formalin in comparison with a vehicle control group, whilemorphine (64 mg/kg p.o.), gabapentin (300 mg/kg p.o.) and duloxetine (10mg/kg p.o.) are administered p.o. 60 minutes before formalin. Data isanalyzed by comparing treated groups with vehicle control groups usingunpaired Mann-Whitney U tests.

Multiple sclerosis can be evaluated by the experimental autoimmuneencephalomyelitis (EAE) model described in [H. Y. Liu et al. J.Neurosci. Res., 2002, 70, 2: 238-48].

Those skilled in the art will recognize that various changes and/ormodifications may be made to aspects or embodiments of this inventionand that such changes and/or modifications may be made without departingfrom the spirit of this invention. Therefore, it is intended that theappended claims cover all such equivalent variations as will fall withinthe spirit and scope of this invention.

Each reference cited in the present application, including literaturereferences, books, patents and patent applications, is incorporatedherein by reference in its entirety.

1-18. (canceled)
 19. A method of treating a disease or disorder, the method comprises administering a therapeutically effective amount of a compound of formula (I):

wherein: R¹ and R² are each independently alkyl, cycloalkyl, ketocycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each is optionally mono-, di-, or tri-substituted independently with alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-R³, —NHR³, —N(alkyl)R³, —C(O)NHR³, —C(O)N(alkyl)R³, —NHC(O)R³, —N(alkyl)C(O)R³, —OH or —OR³, wherein: R³ is C_(j)—C₆alkyl or C₁-C₆cycloalkyl, which is optionally substituted with halogen, C₁-C₃alkoxy, OH, —CN, —NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, C₁-C₃alkylheterocyclyl, C₁-C₃alkylcarbamate, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —NHC₃alkyl, —N(C₁-C₃alkyl)-C(O)—C₁-C₃alkyl, OH, or —O—C₁-C₆alkyl; with the proviso that the compound of formula (I) is not: N,N′-(1,3-adamantylene)bis(3-methoxy-benzamide); N,N′-(1,3-adamantylene)bis(4-ethoxy-benzamide); N,N′-(1,3-adamantylene)bis(4-methoxy-benzamide); N,N′-(1,3-adamantylene)bis(3,4,5-trimethoxybenzamide); N,N′-(1,3-adamantyl ene)bis(2-iodo-benzamide); N,N′-(1,3-adamantylene)bis-benzamide; N,N′-(1,3-adamantylene)bis(3-nitrobenzamide); and N,N′-(1,3-adamantylene)bis-(3-pyridinecarboxamide) or a pharmaceutically acceptable salt thereof to a mammal in need thereof, wherein the disease or disorder is a central nervous system disease or disorder.
 20. The method of claim 19, wherein the mammal is a human.
 21. The method of claim 19, wherein the central nervous system disease or disorder is a cognitive, neurodegenerative, psychiatric or neurological disease or disorder.
 22. The method of claim 21, wherein the cognitive or neurodegenerative disease or disorder is selected from a group consisting of a mood disorder, an anxiety, a schizophrenia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's chorea, amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, a trauma-induced neurodegeneration, AIDS-induced encephalopathy, a non-AIDS-induced encephalopathy, Fragile X syndrome, an autism spectrum disorder, and a combination thereof.
 23. The method claim 22, wherein the mood disorder is a depression.
 24. The method of claim 23, wherein the depression is selected from the group consisting of atypical depression, bipolar depression, unipolar depression, major depression, endogenous depression, involutional depression, reactive depression, postpartum depression, primary depression, psychotic depression, secondary depression, a combination thereof.
 25. The method of claim 22, wherein the anxiety disease or disorder is selected from a group comprising generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, post-traumatic stress disorder, acute stress reaction, an adjustment disorder, a hypochondriacal disorder, separation anxiety disorder, agoraphobia, a specific phobia, anxiety disorder due to general medical condition, substance-induced anxiety disorder, alcohol withdrawal-induced anxiety, and a combination thereof.
 26. The method of claim 19, wherein the central nervous system disease or disorder is a pain disease or disorder selected from the group consisting of inflammatory pain, neuropathic pain and migraine pain.
 27. The method of claim 26, wherein the neuropathic pain or migraine pain disease or disorder is selected from the group consisting of allodynia, hyperalgesic pain, phantom pain, neuropathic pain related to diabetic neuropathy, neuropathic pain related to migraine, and a combination thereof.
 28. The method of claim 19, wherein the central nervous system disease or disorder is a neuronal hyperexcitation state disease or disorder.
 29. The method of claim 28, wherein the neuronal hyperexcitation state disease or disorder is a neuronal hyperexcitation state in medicament withdrawal, a neuronal hyperexcitation state in intoxication, or a combination thereof.
 30. The method of claim 21, wherein at least one symptom of the disease or disorder is treated.
 31. The method of claim 30, wherein the disease or disorder is a depression.
 32. The method of claim 32, wherein the at least one symptom of the depression is depressed feeling, depressed mood, loss of interest or pleasure in some or all activities, changes in appetite, changes in weight, changes in sleep patterns, lack of energy, fatigue, low self esteem, diminished capacity for thinking, concentration, or decisiveness, feelings of hopelessness or worthlessness, psychomotor agitation or retardation, self-reproach, inappropriate guilt, frequent thoughts of death or suicide, plans or attempts to commit suicide, or a combination thereof.
 33. The method of claim 30, wherein the disease or disorder is an anxiety.
 34. The method of claim 33, wherein the at least one symptom of the anxiety is apprehension, fear, trembling, muscle aches, insomnia, abdominal upsets, dizziness, irritability, persistent, recurring thoughts, compulsions, heart palpitations, chest pain, chest discomfort, sweating, tingling sensations, feeling of choking, fear of losing control, flashbacks, nightmares, intrusive thoughts, intrusive recollections, avoidance behaviors, emotional numbing, an inability to sleep, anxious feelings, overactive startle response, hypervigilance, outbursts of anger, faintness, blushing, profuse sweating, gastroesophageal reflux or a combination thereof.
 35. The method of claim 30, wherein the disease or disorder is schizophrenia.
 36. The method of claim 35, wherein the at least one symptom of schizophrenia is a positive symptom selected from the group consisting of hallucination, delusion, paranoia, and a combination thereof.
 37. The method of claim 35, wherein the at least one symptom of schizophrenia is a negative symptom selected from the group consisting of social withdrawal, flat affect, anhedonia, decreased motivation, and a combination thereof.
 38. The method of claim 35, wherein the at least one symptom of schizophrenia is a cognitive symptom selected from the group consisting of severe deficit in attention, severe deficit in object naming, severe deficit in working memory, severe deficit in long-term memory storage, severe deficit in executive functioning, a slowing of information processing, a slowing of neural activity, long term depression, and a combination thereof.
 39. The method of claim 30, wherein the disease or disorder is Parkinson's disease.
 40. The method of claim 39, wherein the at least one symptom of Parkinson's disease is levodopa-induced dyskinesia, poor balance, Parkinsonian gait, bradykinesia, rigidity, tremor, change in speech, loss of facial expression, micrographia, difficulty swallowing, drooling, pain, dementia, confusion, a sleep disturbance, constipation, a skin problem, depression, fear, anxiety, difficulty with memory, slowed thinking, sexual dysfunction, an urinary problem, fatigue, aching, loss of energy, or a combination thereof.
 41. The method of claim 30, wherein the disease or disorder is Alzheimer's disease.
 42. The method of claim 41, wherein the at least one symptom of Alzheimer's disease is impairment in memory, impairment in attention, impairment in judgment, impairment in decision-making, impairment in orientation to physical surroundings, language impairment, impairment in speed-dependent activities, impairment in abstract reasoning, impairment in visuospatial abilities, impairment in executive functioning, impairment in behavioral disturbances, disinterest and passivity, apathy, inappropriate dressing, poor self care, agitation, violent outburst, aggression, depression, anxiety, hallucination, delusion, change in personality, change in mood, dementia, or a combination thereof.
 43. The method of claim 30, wherein the cognitive or neurodegenerative disease or disorder is multiple sclerosis.
 44. The method of claim 43, wherein the at least one symptom of multiple sclerosis is optic neuritis blurred vision, eye pain, loss of color vision, blindness, diplopia double vision, nystagmus jerky eye movements, ocular dysmetria, constant under- or over-shooting eye movements, internuclear ophthalmoplegia, nystagmus, diplopia, movement and sound phosphenes, diplopia, afferent pupillary defect, motor paresis, monoparesis, paraparesis, hemiparesis, quadraparesis plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, footdrop dysfunctional reflexes (MRSs, Babinski's, Hoffman's, Chaddock's), paraesthesia, anaesthesia, neuralgia, neuropathic pain, neurogenic pain, I'hermilte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor-sphincter dyssynergia, erectile dysfunction, anorgasmy, retrograde ejaculation, frigidity, constipation, fecal urgency, depression, cognitive dysfunction, dementia, mood swings, emotional lability, euphoria, bipolar syndrome, anxiety, aphasia, dysphasia, fatigue, uhthoffs symptom, gastroesophageal reflux, a sleeping disorder, or a combination thereof.
 45. A method of treating gastroesophageal reflux, the method comprises administering a therapeutically effective amount of a compound of formula (I):

wherein: R¹ and R² are each independently alkyl, cycloalkyl, ketocycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each is optionally mono-, di-, or tri-substituted independently with alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-R³, —NHR³, —N(alkyl)R³, —C(O)NHR³, —C(O)N(alkyl)R³, —NHC(O)R³, —N(alkyl)C(O)R³, —OH or —OR³, wherein: R³ is C₁-C₆alkyl or C₁-C₆cycloalkyl, which is optionally substituted with halogen, C₁-C₃alkoxy, OH, —CN, —NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, C₁-C₃alkylheterocyclyl, C₁-C₃alkylcarbamate, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —NHC(O)—C₁-C₃alkyl, —N(C₁-C₃alkyl)-C(O)—C₁-C₃alkyl, OH, or —O—C₁-C₆alkyl; with the proviso that the compound of formula (I) is not: N,N′-(1,3-adamantylene)bis(3-methoxy-benzamide); N,N′-(1,3-adamantylene)bis(4-ethoxy-benzamide); N,N′-(1,3-adamantylene)bis(4-methoxy-benzamide); N,N′-(1,3-adamantylene)bis(3,4,5-trimethoxybenzamide); N,N′-(1,3-adamantylene)bis(2-iodo-benzamide); N,N′-(1,3-adamantylene)bis-benzamide; N,N′-(1,3-adamantylene)bis(3-nitrobenzamide); and N,N′-(1,3-adamantylene)bis-(3-pyridinecarboxamide) or a pharmaceutically acceptable salt thereof to a mammal in need thereof.
 46. A method of treating alcohol dependence, the method comprises administering a therapeutically effective amount of a compound of formula (I):

wherein: R¹ and R² are each independently alkyl, cycloalkyl, ketocycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each is optionally mono-, di-, or tri-substituted independently with alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-R³, —NHR³, —N(alkyl)R³, —C(O)NHR³, —C(O)N(alkyl)R³, —NHC(O)R³, —N(alkyl)C(O)R³, —OH or —OR³, wherein: R³ is C₁-C₆alkyl or C₁-C₆cycloalkyl, which is optionally substituted with halogen, C₁-C₃alkoxy, OH, —CN, —NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, C₁-C₃alkylheterocyclyl, C₁-C₃alkylcarbamate, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —NHC(O)—C₁-C₃alkyl, —N(C₁-C₃alkyl)-C(O)—C₁-C₃alkyl, OH, or —O—C₁-C₆alkyl; with the proviso that the compound of formula (I) is not: N,N′-(1,3-adamantylene)bis(3-methoxy-benzamide); N,N′-(1,3-adamantylene)bis(4-ethoxy-benzamide); N,N′-(1,3-adamantylene)bis(4-methoxy-benzamide); N,N′-(1,3-adamantylene)bis(3,4,5-trimethoxybenzamide); N,N′-(1,3-adamantylene)bis(2-iodo-benzamide); N,N′-(1,3-adamantylene)bis-benzamide; N,N′-(1,3-adamantylene)bis(3-nitrobenzamide); and N,N′-(1,3-adamantylene)bis-(3-pyridinecarboxamide) or a pharmaceutically acceptable salt thereof to a mammal in need thereof 